MCL-1 inhibitors

ABSTRACT

The present disclosure generally relates to compounds and pharmaceutical compositions that may be used in methods of treating cancer.

CROSS-REFERENCES TO RELATED APPLICATIONS

This Application is a Continuation of application Ser. No. 16/857,021filed on Apr. 23, 2020 which is a Continuation of application Ser. No.16/410,457 filed on May 13, 2019. Application Ser. No. 16/410,457 claimsthe benefit of U.S. Provisional Application 62/749,918 filed on Oct. 24,2018 and U.S. Provisional Application 62/671,306 filed on May 14, 2018.The entire contents of these applications are incorporated herein byreference in their entirety.

FIELD

This application generally relates to certain compounds that inhibitMCL-1, pharmaceutical compositions comprising the compounds, use of thecompounds to treat cancers, and methods of making the compounds.

BACKGROUND

Apoptosis (programmed cell death) is a process for elimination ofunwanted or potentially dangerous cells from an organism. Avoidance ofapoptosis is critical for the development and sustained growth oftumors. Myeloid cell leukemia 1 protein (MCL-1, also abbreviated Mcl-1or MCL1) is an antiapoptotic member of the Bcl-2 family of proteins.MCL-1 is overexpressed in many cancers. Overexpression of MCL-1 preventscancer cells from undergoing apoptosis. Research has shown that MCL-1inhibitors can be used to treat cancers. Thus, a need exists for newcompounds that inhibit MCL-1.

BRIEF SUMMARY

The foregoing need is addressed by the present disclosure. Inparticular, inhibitors of MCL-1 are provided herein.

In one embodiment, the present disclosure provides a compound accordingto Formula (I):

wherein

is a single or double bond;

-   -   X is O or NR⁷;    -   R¹² is hydrogen or —C(O)R¹;    -   R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocyclyl, 5-10        membered heteroaryl, —OR⁷, or —NR⁸R⁹, wherein        -   said C₁₋₆alkyl, C₁₋₆heteroalkyl, C₂₋₆alkynyl,            C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocyclyl, and            5-10 membered heteroaryl are optionally substituted with 1-5            R¹⁰ groups;    -   R² is hydrogen, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, or        3-12 membered heterocyclyl, wherein        -   said C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, and 3-12            membered heterocyclyl are optionally substituted with 1-5            R¹⁰ groups;    -   R³ and R⁴ are independently hydrogen, C₁₋₆alkyl, —OR⁷,        C₁₋₆heteroalkyl, —NR⁸R⁹, NR⁸C(O)R⁹, —NR⁸C(O)OR⁹, C₆₋₁₀aryl,        C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 3-12 membered        heterocyclyl, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁸R⁹, —OC(O)NR⁸R⁹, —CN,        or —SO₂R⁷, wherein        -   said C₁₋₆alkyl, C₁₋₆heteroalkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,            5-10 membered heteroaryl, and 3-12 membered heterocyclyl are            optionally substituted with 1-5 R¹⁰ groups;    -   R⁵ is hydrogen, C₁₋₆alkyl, —(CH₂CH₂O)_(p)R⁷, C₁₋₆heteroalkyl,        C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, or 3-12        membered heterocyclyl, wherein        -   said C₁₋₆alkyl, C₁₋₆heteroalkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,            5-10 membered heteroaryl, and 3-12 membered heterocyclyl are            optionally substituted with 1-5 R¹⁰ groups;    -   R⁶ is hydrogen or halo;    -   each R⁷ is independently hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, or 5-10        membered heteroaryl, wherein        -   said C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12            membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 membered            heteroaryl are optionally substituted with from 1-5 R¹⁰;    -   each R⁸ and R⁹ are independently hydrogen, C₁₋₆alkyl,        C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered heterocyclyl,        C₆₋₁₀aryl, or 5-10 membered heteroaryl, or R⁸ and R⁹ together        with the atoms to which they are attached form a 3-12 membered        heterocycle, wherein        -   said C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12            membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 membered            heteroaryl are optionally substituted with 1-5 R¹⁰;    -   each R¹⁰ is independently C₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, 5-10        membered heteroaryl, halo, oxo, —OR^(a), —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)_(q)R^(a),        —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂, or two        R¹⁰ groups form a fused, spiro, or bridged C₃₋₁₀ cycloalkyl or        3-12 membered heterocyclyl, wherein        -   each C₁₋₆alkyl, C₁₋₆ heteroalkyl, C₂₋₆alkynyl,            C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocycle, and            5-10 membered heteroaryl is optionally substituted with 1-5            R²⁰ groups;    -   each R^(a) and R^(b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆        alkenyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered        heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, or R^(a) and        R^(b) together with the atoms to which they are attached form a        3-12 membered heterocyclyl wherein        -   said C₁₋₆alkyl, C₂₋₆ alkenyl, C₃₋₁₀cycloalkyl,            C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, 5-10            membered heteroaryl is optionally substituted with 1-5 R²⁰            groups;    -   each R²⁰ is independently C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆        heteroalkyl, 3-12 membered heterocyclyl, C₆-C₁₀ aryl, 5-10        membered heteroaryl, hydroxyl, C₁₋₆ alkoxy, amino, —CN, —C(O)H,        —C(O)NH₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ alkyl)₂, —COOH,        —C(O)C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl, or halogen;    -   n is 0, 1, or 2;    -   p is 0, 1, or 2; and    -   q is 0, 1, or 2;        or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical composition comprising a compoundaccording to Formula (I), or a tautomer or pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient is providedherein.

In some embodiments, a method of inhibiting MCL-1 in a patientcomprising administering a compound according to Formula (I), or atautomer or pharmaceutically acceptable salt thereof, to the patient isprovided herein.

In some embodiments, a method of treating cancer in a patient,comprising administering a compound according to Formula (I), or atautomer or pharmaceutically acceptable salt thereof, to the patient isprovided herein.

DETAILED DESCRIPTION

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

A prefix such as “C_(u-v)” or (C_(u)-C_(v)) indicates that the followinggroup has from u to v carbon atoms, where u and v are integers. Forexample, “C₁₋₆alkyl” indicates that the alkyl group has from 1 to 6carbon atoms.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. Unless chemically or structurally required, nodirectionality is indicated or implied by the order in which a chemicalgroup is written or named.

A squiggly line on a chemical group as shown below, for example,

indicates a point of attachment, i.e., it shows the broken bond by whichthe group is connected to another described group.

The term “substituted” means that one or more hydrogen atoms on ahydrocarbon is replaced with one or more atoms or groups other thanhydrogen, provided that the designated carbon atom's or atoms' normalvalence is not exceeded. A “substituent” is an atom or group thatreplaces a hydrogen atom on a hydrocarbon when it is “substituted.”Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.

The term “about” refers to a value or parameter ±10% the indicatedamount.

As used herein, “alkyl” is a linear or branched saturated monovalenthydrocarbon. Examples of alkyl groups include, but are not limited to,methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, n-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (t-Bu, t-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, 5-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), and 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃.

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond. Examples of alkenyl groups include ethenyl,propenyl, butadienyl (including 1,2-butadienyl, and 1,3-butadienyl).

“Alkoxy” as used herein refers to a radical of the formula —OR_(A) whereR_(A) is an alkyl radical as defined above. Non-limiting examples ofalkoxy include methoxy, ethoxy, propoxy, and butoxy.

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond.

“Aryl” refers to a monoradical or diradical aromatic carbocyclic grouphaving a single ring (e.g., monocyclic) or multiple rings (e.g.,bicyclic or tricyclic) including fused ring systems wherein one or morefused rings is/are fully or partially unsaturated. Non-limiting examplesof aryl groups as used herein include phenyl, naphthyl, fluorenyl,indanyl, tetrahydroindenyl, and anthryl. Aryl, however, does notencompass or overlap in any way with heteroaryl defined below. If one ormore aryl groups are fused with a heteroaryl ring, the resulting ringsystem is heteroaryl. The classification of mono or diradical indicateswhether the aryl group terminates the chain (monoradical) or is within achain (diradical). The above definition does not preclude additionalsubstituents on the aryl group. For example, as used herein, the arylgroup in “A-aryl-B” is a diradical whereas the aryl group in “A-B-aryl”is monoradical, though additional substituents may be present on eacharyl group.

The term “aryloxy” refers to the group —O-aryl.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. Examples of cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Halo” and “halogen” are used herein to refer to fluoro (—F), chloro(—Cl), bromo (—Br) and iodo (—I).

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms of the alkyl areindependently replaced by a halogen substituent, which may be the sameor different. For example, C₁₋₆haloalkyl is a C₁₋₆alkyl wherein one ormore of the hydrogen atoms of the C₁₋₆alkyl have been replaced by a halosubstituent. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, fluorochloromethyl, difluoromethyl,difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, andpentafluoroethyl.

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group. The term“heteroalkyl” includes unbranched or branched saturated chain havingcarbon and heteroatoms selected from nitrogen, sulfur, phosphorus, andoxygen. The heteroatoms within the “heteroalkyl” may be oxidized, e.g.—N(O)—, —S(O)—, —S(O)₂—. Examples of heteroalkyl groups include —OCH₃,—CH₂OCH₃, —SCH₃, —CH₂SCH₃, —NRCH₃, and —CH₂NRCH₃, where R is hydrogen oralkyl.

“Heteroaryl” refers to a monoradical or diradical aromatic group havinga single ring, multiple rings, or multiple fused rings, with one or morering heteroatoms independently selected from nitrogen, oxygen, andsulfur. The heteroatoms within the “heteroaryl” may be oxidized, e.g.,—N(O)—, —S(O)—, —S(O)₂—. The term includes fused ring systems whereinone or more fused rings is/are fully or partially unsaturated. Theclassification of mono or diradical indicates whether the heteroarylgroup terminates the chain (monoradical) or is within a chain(diradical). The above definition does not preclude additionalsubstituents on the heteroaryl group. For example, the heteroaryl groupin “A-heteroaryl-B” is a diradical whereas the heteroaryl group in“A-B-heteroaryl” is monoradical, though additional substituents may bepresent on each heteroaryl group. Heteroaryl does not encompass oroverlap with aryl as defined above. Non-limiting examples of heteroarylgroups include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl.

The term “heteroaryloxy” refers to the group —O-heteroaryl.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical or diradical saturated or unsaturated group having a singlering or multiple condensed rings having one or more heteroatoms selectedfrom nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Theheteroatoms within the “heterocyclyl” may be oxidized, e.g. —N(O)—,—S(O)—, —S(O)₂—. A heterocyclyl may be a single ring or multiple ringswherein the multiple rings may be fused, bridged, or spiro. Anynon-aromatic ring containing at least one heteroatom is considered aheterocyclyl, regardless of the attachment (i.e., can be bound through acarbon atom or a heteroatom). Exemplary heterocyclic groups include, butare not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

The term “cyano” refers to the group —CN.

The term “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The symbol “(±)” is used to designate a racemicmixture where appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results. For purposes of the present disclosure,beneficial or desired results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomassociated with a disease or condition. In one embodiment, “treatment”or “treating” includes one or more of the following: a) inhibiting thedisease or condition (e.g., decreasing one or more symptoms resultingfrom the disease or condition, and/or diminishing the extent of thedisease or condition); b) slowing or arresting the development of one ormore symptoms associated with the disease or condition (e.g.,stabilizing the disease or condition, delaying the worsening orprogression of the disease or condition); and c) relieving the diseaseor condition, e.g., causing the regression of clinical symptoms,ameliorating the disease state, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of a disease or disorder such that theclinical symptoms of the disease or disorder do not develop. Thus,“prevention” relates to administration of a therapy to a subject beforesigns of the disease are detectable in the subject. The subject may bean individual at risk of developing the disease or disorder, such as anindividual who has one or more risk factors known to be associated withdevelopment or onset of the disease or disorder.

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit thedesired biological or medical response, including the amount of acompound that, when administered to a subject for treating a disease, issufficient to effect such treatment for the disease. The effectiveamount will vary depending on the particular compound, andcharacteristics of the subject to be treated, such as age, weight, etc.The effective amount can include a range of amounts. As is understood inthe art, an effective amount may be in one or more doses, i.e., a singledose or multiple doses may be required to achieve the desired treatmentendpoint. An effective amount may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable or beneficial result may be or isachieved. Suitable doses of any co-administered compounds may optionallybe lowered due to the combined action (e.g., additive or synergisticeffects) of the compounds.

As used herein, “co-administration” includes administration of unitdosages of the compounds disclosed herein before or after administrationof unit dosages of one or more additional therapeutic agents, forexample, administration of the compound disclosed herein within seconds,minutes, or hours of the administration of one or more additionaltherapeutic agents. For example, in some embodiments, a unit dose of acompound of the present disclosure is administered first, followedwithin seconds or minutes by administration of a unit dose of one ormore additional therapeutic agents. Alternatively, in other embodiments,a unit dose of one or more additional therapeutic agents is administeredfirst, followed by administration of a unit dose of a compound of thepresent disclosure within seconds or minutes. In some embodiments, aunit dose of a compound of the present disclosure is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of one or more additional therapeutic agents. In otherembodiments, a unit dose of one or more additional therapeutic agents isadministered first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of a compound of the presentdisclosure.

Also provided herein are pharmaceutically acceptable salts, hydrates,solvates, tautomeric forms, polymorphs, and prodrugs of the compoundsdescribed herein. “Pharmaceutically acceptable” or “physiologicallyacceptable” refer to compounds, salts, compositions, dosage forms andother materials which are suitable for veterinary or humanpharmaceutical use.

Compounds described herein may be prepared and/or formulated aspharmaceutically acceptable salts. Pharmaceutically acceptable salts arenon-toxic salts of a free base form of a compound that possesses thedesired pharmacological activity of the free base. These salts may bederived from inorganic or organic acids or bases. For example, acompound that contains a basic nitrogen may be prepared as apharmaceutically acceptable salt by contacting the compound with aninorganic or organic acid. Non-limiting examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, methylsulfonates, propyl sulfonates, besylates,xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists ofother suitable pharmaceutically acceptable salts are found in Remington:The Science and Practice of Pharmacy, 21^(st) Edition, LippincottWiliams and Wilkins, Philadelphia, Pa., 2006.

Non-limiting examples of “pharmaceutically acceptable salts” of thecompounds disclosed herein also include salts derived from anappropriate base, such as an alkali metal (for example, sodium,potassium), an alkaline earth metal (for example, magnesium), ammoniumand NX₄ ⁺ (wherein X is C₁-C₄ alkyl). Also included are base additionsalts, such as sodium or potassium salts.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any said compounds.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

The term “prodrug” as used herein is a biologically inactive derivativeof a drug that upon administration to the human body is converted to thebiologically active parent drug according to some chemical or enzymaticpathway.

LIST OF ABBREVIATIONS AND ACRONYMS

-   -   Abbreviation Meaning    -   ACN Acetonitrile    -   MeTHF 2-methyl tetrahydrofuran    -   Boc t-Butyloxy carbonyl    -   BSA Bovine Serum Albumin    -   calcd or calc'd Calculated    -   DCM Diehl or om ethane    -   DIPEA N,N-Diisopropylethylamine    -   DMAP 4-Dimethylaminopyridine    -   DMF Dimethylformamide    -   DMSO Dimethylsulfoxide    -   Et Ethyl    -   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   EDTA Ethylenediaminetetraacetic acid    -   ESI Electronspray Ionization    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   h or hr(s) Hour(s)    -   i-Pr Isopropyl    -   KHMDS Potassium bis(trimethylsilyl)amide    -   LCMS or Liquid Chromatography Mass Spectrometry    -   LC/MS    -   MeOH Methanol    -   min Minute(s)    -   MS Mass Spectrometry    -   m/z Mass-to-charge ratio    -   NMR Nuclear Magnetic Resonance spectroscopy    -   n-BuLi n-Butyllithium    -   RT or rt Room temperature    -   STAB Sodium triacetoxyborohydride    -   SFC Supercritical Fluid Chromatography    -   TBAF Tetra-n-butylammonium fluoride    -   TBDMS t-Butyl di methyl silyl    -   TBDMSCl t-Butyldimethyl silyl chloride    -   TBSOTf t-Butyldimethylsilyl triflate    -   TEA Trimethylamine    -   TFA Trifluoroacetic acid    -   THF Tetrahydrofuran    -   TLC Thin Layer Chromatography        Compounds

In some embodiments, the present disclosure provides a compoundaccording to Formula (I):

wherein

is a single or double bond;

-   -   X is O or NR⁷;    -   R¹² is hydrogen or —C(O)R¹;    -   R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocyclyl, 5-10        membered heteroaryl, —OR⁷, or —NR⁸R⁹, wherein        -   said C₁₋₆alkyl, C₁₋₆heteroalkyl, C₂₋₆alkynyl,            C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocyclyl, and            5-10 membered heteroaryl are optionally substituted with 1-5            R¹⁰ groups;    -   R² is hydrogen, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, or        3-12 membered heterocyclyl, wherein        -   said C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, and 3-12            membered heterocyclyl are optionally substituted with 1-5            R¹⁰ groups;    -   R³ and R⁴ are independently hydrogen, C₁₋₆alkyl, —OR⁷,        C₁₋₆heteroalkyl, —NR⁸R⁹, NR⁸C(O)R⁹, —NR⁸C(O)OR⁹, C₆₋₁₀aryl,        C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 3-12 membered        heterocyclyl, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁸R⁹, —OC(O)NR⁸R⁹, —CN,        or —SO₂R⁷, wherein        -   said C₁₋₆alkyl, C₁₋₆heteroalkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,            5-10 membered heteroaryl, and 3-12 membered heterocyclyl are            optionally substituted with 1-5 R¹⁰ groups;    -   R⁵ is hydrogen, C₁₋₆alkyl, —(CH₂CH₂O)_(p)R⁷, C₁₋₆heteroalkyl,        C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, or 3-12        membered heterocyclyl, wherein        -   said C₁₋₆alkyl, C₁₋₆heteroalkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl,            5-10 membered heteroaryl, and 3-12 membered heterocyclyl are            optionally substituted with 1-5 R¹⁰ groups;    -   R⁶ is hydrogen or halo;    -   each R⁷ is independently hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, or 5-10        membered heteroaryl, wherein        -   said C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12            membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 membered            heteroaryl are optionally substituted with from 1-5 R¹⁰;    -   each R⁸ and R⁹ are independently hydrogen, C₁₋₆alkyl,        C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered heterocyclyl,        C₆₋₁₀aryl, or 5-10 membered heteroaryl, or R⁸ and R⁹ together        with the atoms to which they are attached form a 3-12 membered        heterocycle, wherein        -   said C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12            membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 membered            heteroaryl are optionally substituted with 1-5 R¹⁰;    -   each R¹⁰ is independently C₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, 5-10        membered heteroaryl, halo, oxo, —OR^(a), —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)_(q)R^(a),        —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂, or two        R¹⁰ groups form a fused, spiro, or bridged C₃₋₁₀ cycloalkyl or        3-12 membered heterocyclyl, wherein        -   each C₁₋₆alkyl, C₁₋₆ heteroalkyl, C₂₋₆alkynyl,            C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocycle, and            5-10 membered heteroaryl is optionally substituted with 1-5            R²⁰ groups;    -   each R^(a) and R^(b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆        alkenyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered        heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, or R^(a) and        R^(b) together with the atoms to which they are attached form a        3-12 membered heterocyclyl wherein        -   said C₁₋₆alkyl, C₂₋₆ alkenyl, C₃₋₁₀cycloalkyl,            C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, 5-10            membered heteroaryl is optionally substituted with 1-5 R²⁰            groups;    -   each R²⁰ is independently C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆        heteroalkyl, 3-12 membered heterocyclyl, C₆-C₁₀ aryl, 5-10        membered heteroaryl, hydroxyl, C₁₋₆ alkoxy, amino, —CN, —C(O)H,        —C(O)NH₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ alkyl)₂, —COOH,        —C(O)C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl, or halogen;    -   n is 0, 1, or 2;    -   p is 0, 1, or 2; and    -   q is 0, 1, or 2;    -   or a tautomer or pharmaceutically acceptable salt thereof.        In some embodiments, the present disclosure provides a compound        of Formula (I) according to Formula (Ia):

or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compoundaccording to Formula (II):

wherein

is a single or double bond;

-   -   R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,        C₆₋₁₀aryl, 5-10 membered heteroaryl, C₁₋₆hydroxyalkyl,        —OC₁₋₆alkyl, —NHC₁₋₆alkyl, —NHC₁₋₆haloalkyl, 4-6 membered        heterocyclyl, C₃₋₆cycloalkyl, —NHC₃₋₁₀cycloalkyl, or        —N(C₁₋₆alkyl)₂, wherein        -   said C₁₋₆alkyl is optionally substituted with C₁₋₆alkoxy,            —N(C₁₋₆alkyl)₂, 5-10 membered heteroaryl, C₃₋₆cycloalkyl,            —SO₂C₁₋₆alkyl, phenyl, 5 membered heteroaryloxy, phenoxy, or            —O-(4-10 membered heterocyclyl),        -   said 5-10 membered heteroaryl is optionally substituted with            1 or 2 substitutents selected from halo, C₁₋₆alkyl, and            C₁₋₆haloalkyl,            -   said 5 membered heteroaryloxy is optionally substituted                with 1-3 C₁₋₆alkyl, and            -   said phenyl is optionally substituted with 1-3 halo or                C₁₋₆haloalkyl;        -   said —NHC₃₋₆cycloalkyl is optionally substituted with            C₁₋₃haloalkyl;        -   said —NHC₁₋₆alkyl is optionally substituted with phenyl, 5-6            membered heteroaryl, or C₃₋₆cycloalkyl wherein            -   said phenyl is optionally substituted with 1-5 halo,            -   said 5 to 6 membered heteroaryl is optionally                substituted with 1-3 halo or C₁₋₆alkyl, and        -   said C₁₋₆hydroxyalkyl is optionally substituted with phenyl;        -   said C₃₋₆cycloalkyl is optionally substituted with 5            membered heteroaryl, wherein            -   said 5 membered heteroaryl is optionally substituted                with C₁₋₆alkyl;        -   said —OC₁₋₆alkyl is optionally substituted with 5 membered            heteroaryl, wherein            -   said 5 membered heteroaryl is optionally substituted                with C₁₋₆alkyl;        -   said 5-10 membered heteroaryl is optionally substituted with            C₁₋₆alkyl;    -   R² is hydrogen or C₁₋₆alkyl;    -   R³ is hydrogen or C₁₋₆alkyl;    -   R⁴ is hydrogen; and    -   R⁵ is hydrogen or C₁₋₆alkyl, wherein        -   said C₁₋₆alkyl is optionally substituted with 5-6 membered            heterocyclyl;            or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (II) according to Formula (IIa):

or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), or Formula (IIa), wherein:

-   -   R² is hydrogen or C₁₋₃alkyl;    -   R³ is hydrogen or C₁₋₃alkyl;    -   R⁴ is hydrogen; and    -   R⁵ is C₁₋₃alkyl, wherein        -   said C₁₋₃alkyl is optionally substituted with a 5-6 membered            heterocyclyl;            or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), or Formula (IIa), wherein:

-   -   R² is hydrogen, methyl, or ethyl;    -   R³ is hydrogen or methyl;    -   R⁴ is hydrogen; and    -   R⁵ is hydrogen, methyl,

or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), or Formula (IIa), wherein:

-   -   R² is hydrogen; and    -   R³ is C₁₋₃alkyl;        or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), or Formula (IIa), wherein:

-   -   R² is C₁₋₃alkyl; and    -   R³ is hydrogen;        or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), or Formula (IIa), wherein:

-   -   R² is hydrogen; and    -   R³ is hydrogen;        or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), or Formula (IIa), wherein:

-   -   R² is C₁₋₃alkyl; and    -   R³ is C₁₋₃alkyl;        or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compoundaccording to Formula (III), or a pharmaceutically acceptable saltthereof:

wherein

is a single or double bond;

-   -   R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocyclyl, 5-10        membered heteroaryl, —OR⁷, or —NR⁸R⁹;        -   wherein said C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl,            C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered            heterocyclyl, and 5-10 membered heteroaryl of R¹ are            independently optionally substituted with 1-5 R¹⁰ groups;    -   each R², R³, R⁴, and R⁵ is independently hydrogen or C₁₋₆alkyl;    -   R⁶ is hydrogen or halo;    -   each R⁷ is independently hydrogen, or C₁₋₆alkyl, wherein        -   said C₁₋₆alkyl is optionally substituted with from 1-5 R¹⁰;    -   each R⁸ and R⁹ is independently hydrogen, C₁₋₆alkyl,        C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered heterocyclyl,        C₆₋₁₀aryl, or 5-10 membered heteroaryl, or R⁸ and R⁹ together        with the atoms to which they are attached form a 3-12 membered        heterocycle, wherein        -   said C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12            membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 membered            heteroaryl of R⁸ and R⁹ are independently optionally            substituted with 1-5 R¹⁰;    -   each R¹⁰ is independently C₁₋₆alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, 5-10        membered heteroaryl, halo, oxo, —OR^(a), —C(O)R^(a),        —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b), —S(O)_(q)R^(a),        —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂, or two        R¹⁰ groups form a fused, spiro, or bridged C₃₋₁₀ cycloalkyl or        3-12 membered heterocyclyl, wherein        -   each C₁₋₆alkyl, C₁₋₆ heteroalkyl, C₂₋₆alkynyl,            C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocycle, and            5-10 membered heteroaryl of R¹⁰ is independently optionally            substituted with 1-5 R²⁰ groups;    -   each R^(a) and R^(b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆        alkenyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered        heterocyclyl, C₆₋₁₀aryl, or 5-10 membered heteroaryl, or R^(a)        and R^(b) together with the atoms to which they are attached        form a 3-12 membered heterocyclyl wherein        -   said each C₁₋₆alkyl, C₂₋₆ alkenyl, C₃₋₁₀cycloalkyl,            C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, 5-10            membered heteroaryl of R^(a) and R^(b) is independently            optionally substituted with 1-5 R²⁰ groups;    -   each R²⁰ is independently C₁₋₆ alkyl, C₃₋₁₀cycloalkyl,        C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, 5-10        membered heteroaryl, hydroxyl, C₁₋₆ alkoxy, amino, —CN, —C(O)H,        —C(O)NH₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ alkyl)₂, —COOH,        —C(O)C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, or halogen;    -   n is 0, 1, or 2; and    -   q is 0, 1, or 2.

In some embodiments, the present disclosure provides a compound ofFormula (III), according to Formula (IIIa):

or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (III), or a pharmaceutically acceptable salt thereof, accordingto Formula (IIIb):

wherein: R¹ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, —NHC₁₋₆alkyl, —NHC₁₋₆haloalkyl, 4-6 membered heterocyclyl,C₃₋₆cycloalkyl, —NHC₃₋₁₀cycloalkyl, or —NH(4-6 membered heterocyclyl);

-   -   each C₁₋₆alkyl and —NHC₁₋₆alkyl of R¹ is independently        optionally substituted with 1-3 substituents independently        selected from hydroxyl, C₁₋₆alkoxy, 5-10 membered heteroaryl,        C₃₋₆cycloalkyl, phenyl, or —O-(4-10 membered heterocyclyl);        -   wherein each 5-10 membered heteroaryl, C₃₋₆cycloalkyl,            phenyl, and —O-(4-10 membered heterocyclyl) is independently            optionally substituted with 1-4 substituents independently            selected from halo, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each C₆₋₁₀aryl and 5-10 membered heteroaryl of R¹ is optionally        substituted with 1-3 substituents independently selected from        halo, hydroxyl, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,        4-6 membered heterocyclyl, and C₃₋₆cycloalkyl; and    -   each 4-6 membered heterocyclyl, C₃₋₆cycloalkyl,        —NHC₃₋₁₀cycloalkyl, and —NH(4-6 membered heterocyclyl) of R¹ is        optionally substituted with 1 to 3 substituents independently        selected from halo, oxo, hydroxyl, —CN, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —C(O)OR^(a), C₆₋₁₀aryl, 5-10        membered heteroaryl, 4-6 membered heterocyclyl, and        C₃₋₆cycloalkyl;        -   wherein each C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-6            membered heterocyclyl, and C₃₋₆cycloalkyl is independently            optionally substituted with 1-3 substituents independently            selected from halo, C₁₋₄alkyl, and C₁₋₄haloalkyl;    -   each R², R³, R⁴, and R⁵ is independently hydrogen or C₁₋₆alkyl;        and    -   R⁶ is hydrogen or halo.

In some embodiments, the present disclosure provides a compound ofFormula (IIIc), or a pharmaceutically acceptable salt thereof:

each R¹, R², R³, R⁴, R⁵, and R⁶ is defined as above, or elsewhere inthis disclosure.

In some embodiments, the present disclosure provides a compound ofFormula (IIId), or a pharmaceutically acceptable salt thereof:

each R¹, R², R³, R⁴, R⁵, and R⁶ is defined as above, or elsewhere inthis disclosure.

In some embodiments, the present disclosure provides a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof:

wherein: R¹ is C₃₋₁₀cycloalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl,or 5-10 membered heteroaryl;

-   -   wherein R¹ is independently optionally substituted with 1-4 R¹⁰;        -   wherein each R¹⁰ is independently selected from halo,            hydroxyl, —CN, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl,            and 3-12 membered heterocyclyl;        -   wherein C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl and 3-12            membered heterocyclyl of R¹⁰ are independently optionally            substituted with 1-4 substituents independently selected            from halo, C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄heteroalkyl;    -   R² is hydrogen, C₁₋₆alkyl, or C₁₋₆heteroalkyl;        -   wherein C₁₋₆alkyl and C₁₋₆heteroalkyl of R² is optionally            substituted with 1-3 substituents independently selected            from halo, oxo, and hydroxyl;    -   R³ and R⁴ are independently hydrogen, C₁₋₆alkyl,        C₁₋₆heteroalkyl, —OR⁷, or —SO₂R⁷;        -   wherein C₁₋₆alkyl and C₁₋₆heteroalkyl of R³ and R⁴ are            independently optionally substituted with 1-3 substituents            independently selected from halo, oxo, C₃₋₆ cycloalkyl, 4-6            membered heterocyclyl, C₆₋₁₀aryl, and 5-10 membered            heteroaryl;        -   wherein C₃₋₆cycloalkyl, 4-6 membered heterocyclyl,            C₆₋₁₀aryl, and 5-10 membered heteroaryl are independently            optionally substituted with 1-3 substituents independently            selected from halo, C₁₋₄alkyl, and C₁₋₄heteroalkyl;    -   R⁵ is hydrogen, C₁₋₆alkyl, or C₁₋₆heteroalkyl;        -   wherein C₁₋₆alkyl and C₁₋₆heteroalkyl of R⁵ are optionally            substituted with 1-3 substituents independently selected            from halo, oxo, C₃₋₆cycloalkyl, and 4-6 membered            heterocyclyl; and    -   R⁷ is independently hydrogen, C₁₋₆alkyl, C₁₋₆heteroalkyl,        C₃₋₁₀cycloalkyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl, or 5-10        membered heteroaryl;        -   wherein C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, 3-10            membered heterocyclyl, C₆₋₁₀aryl, and 5-10 membered            heteroaryl of R⁷ are optionally substituted with 1-4            substituents independently selected from halo, oxo,            C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄heteroalkyl.

In some embodiments, the present disclosure provides a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, accordingto Formula (IVa):

wherein: R¹ is 3-12 membered heterocyclyl, or 5-10 membered heteroaryl;

-   -   wherein R¹ is independently optionally substituted with 1-4 R¹⁰;        -   wherein each R¹⁰ is independently selected from halo,            hydroxyl, —CN, C₁₋₄alkyl, C₁₋₄alkoxyl, C₃₋₆cycloalkyl, and            3-6 membered heterocyclyl;    -   each R², R³, and R⁴ is independently hydrogen, C₁₋₄alkyl, or        C₁₋₄alkoxyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein heterocyclyl groups are partiallyunsaturated ring systems containing one or more double bonds. In someembodiments, heterocyclyl groups are fused ring systems with onearomatic ring and one non-aromatic ring, but not fully aromatic ringsystems.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R² is hydrogen.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R² is C₁₋₃alkyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R² is methyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R³ is C₁₋₃alkyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R³ is methyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R⁴ is hydrogen.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R⁵ is C₁₋₃alkyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R⁵ is methyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R⁶ is Cl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), or Formula (IIa), wherein—C(O)R¹ is selected from the group consisting of

or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), or Formula (IIIb), or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from:

In some embodiments, the present disclosure provides a compound ofFormula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or pharmaceutically acceptable salt thereof, wherein R¹ is 3-12 memberedheterocyclyl, or 5-10 membered heteroaryl, optionally substituted with1-2 R¹⁰.

In some embodiments, the present disclosure provides a compound ofFormula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom:

each of which is optionally substituted with 1-2 R¹⁰. In someembodiments, each R¹⁰ is independently selected from —CH₃, —CHF₂, and—OCH₃.

In some embodiments, R¹ is

optionally substituted with 1-2 R¹⁰. In some embodiments, R¹ is

optionally substituted with 1-2 R¹⁰. In some embodiments, R¹⁰ isindependently selected from C₁₋₄alkyl, and C₁₋₄alkoxyl. In someembodiments, R¹⁰ is independently selected from —CH₃, and —OCH₃. In someembodiments, R¹ is

substituted with —CH₃, and —OCH₃.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (me), Formula (IIId), Formula(IV), or Formula (IVa), or pharmaceutically acceptable salt thereof,wherein R² is hydrogen or C₁₋₃alkyl. In some embodiments, R² is selectedfrom hydrogen and methyl. In some embodiments, R² is hydrogen. In someembodiments, R² is methyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (me), Formula (IIId), Formula(IV), or Formula (IVa), or pharmaceutically acceptable salt thereof,wherein R³ is hydrogen or C₁₋₃alkyl. In some embodiments, R³ is selectedfrom hydrogen and methyl. In some embodiments, R³ is methyl. In someembodiments, R³ is hydrogen.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (me), Formula (IIId), Formula(IV), or Formula (IVa), or pharmaceutically acceptable salt thereof,wherein R⁴ is hydrogen, C₁₋₃alkyl, or C₁₋₃alkoxyl. In some embodiments,R⁴ is selected from hydrogen, methyl, and —OCH₃. In some embodiments, R⁴is hydrogen. In some embodiments, R⁴ is —OCH₃. In some embodiments, R⁴is methyl.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (me), Formula (IIId), Formula(IV), or Formula (IVa), or pharmaceutically acceptable salt thereof,wherein R² and R⁴ are hydrogen, and R³ is methyl. In some embodiments,R² and R³ are methyl, and R⁴ is hydrogen. In some embodiments, R² ishydrogen, R³ is methyl, and R⁴ is —OCH₃.

In some embodiments, the present disclosure provides a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (me), Formula (IIId), or Formula(IV), or pharmaceutically acceptable salt thereof, wherein R⁵ ishydrogen or C₁₋₃alkyl. In some embodiments, R⁵ is methyl. In someembodiments, R⁵ is hydrogen.

In some embodiments, the present disclosure provides a compound selectedfrom examples 1-464.

In some embodiments, the present disclosure provides a compound selectedfrom examples 1-154.

In some embodiments, the present disclosure provides a compound selectedfrom examples 155-464.

In some embodiments, the present disclosure provides a compound selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selectedfrom:

In some embodiments, the present disclosure provides a compound selectedfrom:

In some embodiments, isotopically labeled forms of the compounds ofFormula (I), Formula (Ia), Formula (II), or Formula (IIa) are providedherein. In some embodiments, isotopically labeled forms of the compoundsof Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula(III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId),Formula (IV), or Formula (IVa), are provided herein. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an isotope having aselected atomic mass or mass number. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an isotope having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as, but not limited to ²H(deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S,³⁶Cl, and ¹²⁵I. Various isotopically labeled compounds of the presentdisclosure, for example those into which radioactive isotopes such as³H, ¹³C and ¹⁴C are incorporated, are within the ambit of the presentdisclosure. Such isotopically labelled compounds may be useful inmetabolic studies, reaction kinetic studies, detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays or in treatment of patients. Such isotopicallylabeled analogs of compounds of the present disclosure may also beuseful for treatment of diseases disclosed herein because they mayprovide improved pharmacokinetic and/or pharmacodynamic properties overthe unlabeled forms of the same compounds. Such isotopically leveledforms of or analogs of compounds herein are within the ambit of thepresent disclosure. One of skill in the art is able to prepare and usesuch isotopically labeled forms following procedures for isotopicallylabeling compounds or aspects of compounds to arrive at isotopic orradiolabeled analogs of compounds disclosed herein.

The compounds disclosed herein may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.The present disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).Likewise, all tautomeric forms are also intended to be included.

In certain embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the pharmaceuticalcomposition comprises one or more additional therapeutic agents, asdescribed in more detail below.

Pharmaceutical compositions comprising the compounds disclosed herein,or pharmaceutically acceptable salts thereof, may be prepared with oneor more pharmaceutically acceptable excipients which may be selected inaccord with ordinary practice. “Pharmaceutically acceptable excipient”includes without limitation any adjuvant, carrier, excipient, glidant,sweetening agent, diluent, preservative, dye/colorant, flavor enhancer,surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

In certain embodiments, pharmaceutical compositions are provided as asolid dosage form, including a solid oral dosage form, such as a tablet.Tablets may contain excipients including glidants, fillers, binders andthe like. Aqueous compositions may be prepared in sterile form, and whenintended for delivery by other than oral administration generally may beisotonic. All compositions may optionally contain excipients such asthose set forth in the Rowe et al, Handbook of PharmaceuticalExcipients, 6^(th) edition, American Pharmacists Association, 2009.Excipients can include ascorbic acid and other antioxidants, chelatingagents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike.

Pharmaceutical compositions disclosed herein include those suitable forvarious administration routes, including oral administration. Thecompositions may be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Such methodsinclude the step of bringing into association the active ingredient(e.g., a compound of the present disclosure or a pharmaceutical saltthereof) with one or more pharmaceutically acceptable excipients. Thecompositions may be prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid excipients or finelydivided solid excipients or both, and then, if necessary, shaping theproduct. Techniques and formulations generally are found in Remington:The Science and Practice of Pharmacy, 21^(st) Edition, LippincottWiliams and Wilkins, Philadelphia, Pa., 2006.

Compositions described herein that are suitable for oral administrationmay be presented as discrete units (a unit dosage form) including butnot limited to capsules, cachets or tablets each containing apredetermined amount of the active ingredient. In one embodiment, thepharmaceutical composition is a tablet.

Pharmaceutical compositions disclosed herein comprise one or morecompounds disclosed herein, or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable excipient andoptionally other therapeutic agents. Pharmaceutical compositionscontaining the active ingredient may be in any form suitable for theintended method of administration. When used for oral use for example,tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, syrups or elixirsmay be prepared. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore excipients including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipients which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,lactose monohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that may be combined with the inactiveingredients to produce a dosage form may vary depending upon theintended treatment subject and the particular mode of administration.For example, in some embodiments, a dosage form for oral administrationto humans may contain approximately 1 to 1000 mg of active materialformulated with an appropriate and convenient amount of apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutically acceptable excipient varies from about 5 to about 95%of the total compositions (weight:weight).

Methods

In some embodiments, the present disclosure provides a method ofinhibiting MCL-1. In some embodiments, the present disclosure provides amethod of inhibiting MCL-1 in an individual (e.g., a human) comprisingadministering a compound of Formula (I), or a tautomer orpharmaceutically acceptable salt thereof, to the individual.

In some embodiments, the present disclosure provides a method oftreating or preventing cancer. In certain embodiments, the presentdisclosure provides a method of treating or preventing cancer comprisingadministering to a patient a therapeutically effective amount a compoundof Formula (I), or a tautomer or pharmaceutically acceptable saltthereof, to the individual. In some embodiments, the cancer is ahematologic malignancy. In some embodiments, the cancer is multiplemyeloma. In some embodiments, the cancer is selected from the groupconsisting of breast cancer, colorectal cancer, skin cancer, melanoma,ovarian cancer, kidney cancer, small cell lung cancer, non-small celllung cancer, lymphoma, and leukemia.

Compounds disclosed herein can be administered by any route appropriatefor use in a method described herein. Suitable routes include oral,rectal, nasal, topical (including buccal and sublingual), transdermal,vaginal and parenteral (including subcutaneous, intramuscular,intravenous, intradermal, intrathecal and epidural), and the like.

Compounds disclosed herein may be administered to an individual inaccordance with an effective dosing regimen for a desired period of timeor duration, such as at least one week, at least about one month, atleast about 2 months, at least about 3 months, at least about 6 months,or at least about 12 months or longer. In one variation, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

Therapeutically effective amounts of compounds disclosed herein are fromabout 0.00001 mg/kg body weight per day to about 10 mg/kg body weightper day, such as from about 0.0001 mg/kg body weight per day to about 10mg/kg body weight per day, or such as from about 0.001 mg/kg body weightper day to about 1 mg/kg body weight per day, or such as from about 0.01mg/kg body weight per day to about 1 mg/kg body weight per day, or suchas from about 0.05 mg/kg body weight per day to about 0.5 mg/kg bodyweight per day, or such as from about 0.3 μg to about 30 mg per day, orsuch as from about 0.3 μg to about 30 mg per day.

A compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa),Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula(IIId), Formula (IV), or Formula (IVa), or a tautomer orpharmaceutically acceptable salt thereof, may be combined with one ormore additional therapeutic agents in any dosage amount of the compoundof the present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts of the compound of Formula (I),Formula (Ia), Formula (II), or Formula (IIa), or a tautomer orpharmaceutically acceptable salt thereof, can range from about 0.01 mgper dose to about 1000 mg per dose, such as from about 0.01 mg per doseto about 100 mg per dose, or such as from about 0.1 mg per dose to about100 mg per dose, or such as from about 1 mg per dose to about 100 mg perdose, or such as from about 1 mg per dose to about 10 mg per dose. Othertherapeutically effective amounts of the compound of Formula (I),Formula (Ia), Formula (II), or Formula (IIa) are about 1 mg per dose, orabout 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Othertherapeutically effective amounts of the compound of Formula (I),Formula (Ia), Formula (II), or Formula (IIa) are about 100 mg per dose,or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about500 mg per dose.

Therapeutically effective amounts of the compound of Formula (I),Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula(IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), orFormula (IVa), or a tautomer or pharmaceutically acceptable saltthereof, can range from about 0.01 mg per dose to about 1000 mg perdose, such as from about 0.01 mg per dose to about 100 mg per dose, orsuch as from about 0.1 mg per dose to about 100 mg per dose, or such asfrom about 1 mg per dose to about 100 mg per dose, or such as from about1 mg per dose to about 10 mg per dose. Other therapeutically effectiveamounts of the compound of Formula (I), Formula (Ia), Formula (II),Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula(IIIc), Formula (IIId), Formula (IV), or Formula (IVa), are about 1 mgper dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose.Other therapeutically effective amounts of the compound of Formula (I),Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula(IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), orFormula (IVa), are about 100 mg per dose, or about 125, 150, 175, 200,225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose.

A single dose can be administered hourly, daily, or weekly. For example,a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12,16 or once every 24 hours. A single dose can also be administered onceevery 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can alsobe administered once every 1 week, 2, 3, or once every 4 weeks. Incertain embodiments, a single dose can be administered once every week.A single dose can also be administered once every month. In someembodiments, a compound disclosed herein is administered once daily in amethod disclosed herein. In some embodiments, a compound disclosedherein is administered twice daily in a method disclosed herein.

The frequency of dosage of a compound disclosed herein will bedetermined by the needs of the individual patient and can be, forexample, once per day or twice, or more times, per day. Administrationof a compound continues for as long as necessary to treat cancer. Forexample, a compound disclosed herein can be administered to a humanhaving cancer for a period of from 20 days to 180 days or, for example,for a period of from 20 days to 90 days or, for example, for a period offrom 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of a compounddisclosed herein, followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of a compound every other day, orthree times per week. Again by way of non-limiting example, a patientcan receive a dose of a compound each day for a period of from 1 to 14days, followed by a period of 7 to 21 days during which the patient doesnot receive a dose of the compound, followed by a subsequent period(e.g., from 1 to 14 days) during which the patient again receives adaily dose of the compound. Alternating periods of administration of thecompound, followed by non-administration of the compound, can berepeated as clinically required to treat the patient.

Combination Therapy

Also provided are methods of treatment in which a compound of Formula(I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula(IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), orFormula (IVa), or a tautomer or pharmaceutically acceptable saltthereof, is given to a patient in combination with one or moreadditional active agents or therapy.

Thus in one embodiment, a method of treating cancer and/or diseases orsymptoms that co-present or are exacerbated or triggered by the cancere.g., an allergic disorder and/or an autoimmune and/or inflammatorydisease, and/or an acute inflammatory reaction, comprises administeringto a patient in need thereof an effective amount of a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula(IV), or Formula (IVa), or a tautomer or pharmaceutically acceptablesalt thereof, optionally in combination with an additional agent (e.g.,a second, third, fourth or fifth active agent) that can be useful fortreating a cancer, an allergic disorder and/or an autoimmune and/orinflammatory disease, and/or an acute inflammatory reaction incident toor co-presenting with a cancer. Treatment with the second, third, fourthor fifth active agent may be prior to, concomitant with, or followingtreatment with a compound of Formula (I), Formula (Ia), Formula (II),Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula(IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer orpharmaceutically acceptable salt thereof. In one embodiment, a compoundof Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula(III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId),Formula (IV), or Formula (IVa), or a tautomer or pharmaceuticallyacceptable salt thereof is combined with another active agent in asingle dosage form. Suitable antitumor or anticancer therapeutics thatmay be used in combination with a compound of Formula (I), Formula (Ia),Formula (II), or Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or a tautomer or pharmaceutically acceptable salt thereof include, butare not limited to, chemotherapeutic agents, for example mitomycin C,carboplatin, taxol, cisplatin, paclitaxel, etoposide, doxorubicin, or acombination comprising at least one of the foregoing chemotherapeuticagents. Radiotherapeutic antitumor agents may also be used, alone or incombination with chemotherapeutic agents.

A compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa),Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula(IIId), Formula (IV), or Formula (IVa), or a tautomer orpharmaceutically acceptable salt thereof can be useful aschemo-sensitizing agents, and thus, can be useful in combination withother chemotherapeutic drugs, in particular, drugs that induceapoptosis. Thus, in one embodiment, the present disclosure provides amethod for increasing sensitivity of cancer cells to chemotherapy,comprising administering to a patient in need of or undergoingchemotherapy, a chemotherapeutic agent together with a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula(IV), or Formula (IVa), or a tautomer or pharmaceutically acceptablesalt thereof in an amount sufficient to increase the sensitivity ofcancer cells to the chemotherapeutic agent.

Examples of other chemotherapeutic drugs that can be used in combinationwith compounds of Formula (I), Formula (Ia), Formula (II), Formula(IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc),Formula (IIId), Formula (IV), or Formula (IVa), or a tautomer orpharmaceutically acceptable salt thereof include topoisomerase Iinhibitors (camptothesin or topotecan), topoisomerase II inhibitors(e.g., daunomycin and etoposide), alkylating agents (e.g.,cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g.,taxol and vinblastine), and biological agents (e.g., antibodies such asanti CD20 antibody, IDEC 8, immunotoxins, and cytokines).

In some embodiments, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is used incombination with Rituxan® (Rituximab) and/or other agents that work byselectively depleting CD20+ B-cells.

Included herein are methods of treatment in which a compound of Formula(I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula(IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), orFormula (IVa), or a tautomer or pharmaceutically acceptable salt thereofis administered in combination with an anti-inflammatory agent.Anti-inflammatory agents include but are not limited to NSAIDs,non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, goldcompounds, corticosteroids, methotrexate, tumor necrosis factor receptor(TNF) receptors antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be chosen from cortisone, dexamethasone,methylprednisolone, prednisolone, prednisolone sodium phosphate, andprednisone. In some embodiments, the anti-inflammatory therapeutic agentis a gold compound such as gold sodium thiomalate or auranofin. In someembodiments, the anti-inflammatory agent is a metabolic inhibitor suchas a dihydrofolate reductase inhibitor, such as methotrexate or adihydroorotate dehydrogenase inhibitor, such as leflunomide.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is used incombination with at least one anti-inflammatory compound that is ananti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNFantagonist, such as entanercept, or infliximab, which is an anti-TNFalpha monoclonal antibody.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is used incombination with at least one active agent that is an immunosuppressantcompound such as methotrexate, leflunomide, cyclosporine, tacrolimus,azathioprine, or mycophenolate mofetil.

In other embodiments, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is used incombination with one or more phosphatidylinositol 3-kinase (PI3K)inhibitors, including for example, Compounds A, B and C (whosestructures are provided below), or a pharmaceutically acceptable saltthereof.

Compounds A, B and C are disclosed in WO2015/017460 and WO2015/100217.Additional examples of PI3K inhibitors include, but are not limited to,ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235,buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY80-6946), duvelisib, GDC-0941, GDC-0980, GSK2636771, GSK2269557,idelalisib (Zydelig®), IPI-145, IPI-443, IPI-549, KAR4141, LY294002,LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, rigosertib, RP5090,taselisib, TG100115, TGR-1202, TGX221, WX-037, X-339, X-414, XL147(SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compoundsdescribed in WO 2005/113556 (ICOS), WO 2013/052699 (Gilead Calistoga),WO 2013/116562 (Gilead Calistoga), WO 2014/100765 (Gilead Calistoga), WO2014/100767 (Gilead Calistoga), and WO 2014/201409 (Gilead Sciences).

In yet another embodiment, a compound of Formula (I), Formula (Ia),Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or a tautomer or pharmaceutically acceptable salt thereof may be used incombination with Spleen Tyrosine Kinase (SYK) Inhibitors. Examples ofSYK inhibitors include, but are not limited to,6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607),entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112,R343, tamatinib (R406), and those described in U.S. Pat. No. 8,450,321(Gilead Connecticut) and those described in U.S. 2015/0175616.

In yet another embodiment, a compound of Formula (I), Formula (Ia),Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or a tautomer or pharmaceutically acceptable salt thereof may be used incombination with Tyrosine-kinase Inhibitors (TKIs). TKIs may targetepidermal growth factor receptors (EGFRs) and receptors for fibroblastgrowth factor (FGF), platelet-derived growth factor (PDGF), and vascularendothelial growth factor (VEGF). Examples of TKIs include, but are notlimited to, afatinib, ARQ-087, asp5878, AZD3759, AZD4547, bosutinib,brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib,dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib(ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src),lapatinib, lestaurtinib, midostaurin, nintedanib, ODM-203, osimertinib(AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib,sulfatinib (HMPL-012), sunitinib, and TH-4000.

In yet other embodiments, a compound of Formula (I), Formula (Ia),Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or a tautomer or pharmaceutically acceptable salt thereof may be used incombination with one or more inhibitors of lysyl oxidase-like 2 (LOXL)or a substance that binds to LOXL, including for example, a humanizedmonoclonal antibody (mAb) with an immunoglobulin IgG4 isotype directedagainst human LOXL2. Examples of LOXL inhibitors include, but are notlimited to, the antibodies described in WO 2009/017833 (ArrestoBiosciences). Examples of LOXL2 inhibitors include, but are not limitedto, the antibodies described in WO 2009/017833 (Arresto Biosciences), WO2009/035791 (Arresto Biosciences), and WO 2011/097513 (GileadBiologies).

In yet another embodiment, a compound of Formula (I), Formula (Ia),Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or a tautomer or pharmaceutically acceptable salt thereof may be used incombination with Toll-like receptor 8 (TLR8) inhibitors. Examples ofTLR8 inhibitors include, but are not limited to, E-6887, IMO-4200,IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463,and VTX-763.

In yet another embodiment, a compound of Formula (I), Formula (Ia),Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or a tautomer or pharmaceutically acceptable salt thereof may be used incombination with Toll-like receptor (TLR9) inhibitors. Examples of TLR9inhibitors include, but are not limited to, IMO-2055, IMO-2125,lefitolimod, litenimod, MGN-1601, and PUL-042.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with a BTK (Bruton's Tyrosine kinase)inhibitor. An example of such BTK inhibitor is a compound disclosed inU.S. Pat. No. 7,405,295. Additional examples of BTK inhibitors include,but are not limited to,(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one,acalabrutinib (ACP-196), BGB-3111, HM71224, ibrutinib, M-2951,tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), and TAK-020.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with a BET inhibitor. An example ofsuch BET inhibitor is a compound disclosed in WO2014/182929, the entirecontents of which are incorporated herein by reference.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with a TBK (Tank Binding kinase)inhibitor. An example of such TBK inhibitor is a compound disclosed inWO2016/049211.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with an OX40 inhibitor. An example ofsuch OX40 inhibitor is a compound disclosed in U.S. Pat. No. 8,450,460,the entire contents of which are incorporated herein by reference.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with a JAK-1 inhibitor. An example ofsuch JAK-1 inhibitor is a compound disclosed in WO2008/109943. Examplesof other JAK inhibitors include, but are not limited to, AT9283,AZD1480, baricitinib, BMS-911543, fedratinib, fdgotinib (GLPG0634),gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387),NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib,tofacitinib (formerly tasocitinib), and XL019.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with anIndoleamine-pyrrole-2,3-dioxygenase (IDO) inhibitors. An example of suchIDO inhibitor is a compound disclosed in WO2016/186967. In oneembodiment, the compounds of Formula (I), Formula (Ia), Formula (II), orFormula (IIa) are useful for the treatment of cancer in combination withIDO1 inhibitors including but not limited to BLV-0801, epacadostat,F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218,NLG-919-based vaccine, PF-06840003, pyranonaphthoquinone derivatives(SN-35837), resminostat, SBLK-200802, and shIDO-ST.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with a Mitogen-activated ProteinKinase (MEK) Inhibitor. MEK inhibitors useful for combination treatmentwith a compound(s) of Formula (I), Formula (Ia), Formula (II), Formula(IIa), Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc),Formula (IIId), Formula (IV), or Formula (IVa), includes antroquinonol,binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib(AZD6244), sorafenib, trametinib (GSK1120212), uprosertib andtrametinib.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with an Apoptosis Signal-RegulatingKinase (ASK) Inhibitors: ASK inhibitors include but are not limited tothose described in WO 2011/008709 (Gilead Sciences) and WO 2013/112741(Gilead Sciences) including, for example, selonsertib.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof may be combinedwith Cluster of Differentiation 47 (CD47) inhibitors. Examples of CD47inhibitors include, but are not limited to anti-CD47 mAbs (Vx-1004),anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanizedanti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof may be combinedwith Cyclin-dependent Kinase (CDK) Inhibitors. CDK inhibitors includeinhibitors of CDK 1, 2, 3, 4, 6 and 9, such as abemaciclib, alvocidib(HMR-1275, flavopiridol), AT-7519, FLX-925, LEE001, palbociclib,ribociclib, rigosertib, selinexor, UCN-01, and TG-02.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof may be combinedwith Discoidin Domain Receptor (DDR) Inhibitors for the treatment ofcancer. DDR inhibitors include inhibitors of DDR1 and/or DDR2. Examplesof DDR inhibitors include, but are not limited to, those disclosed in WO2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical),US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013/027802 (ChugaiPharmaceutical), and WO 2013/034933 (Imperial Innovations).

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof may be combinedwith Histone Deacetylase (HDAC) Inhibitors such as those disclosed inU.S. Pat. No. 8,575,353 and equivalents thereof. Additional examples ofHDAC inhibitors include, but are not limited to, abexinostat, ACY-241,AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907,entinostat, givinostat, mocetinostat, panobinostat, pracinostat,quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproicacid (VAL-001), and vorinostat.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof is useful for thetreatment of cancer in combination with a standard of care in thetreatment of the respective cancer. One of skill in the art is aware ofthe standard of care as of a given date in the particular field ofcancer therapy or with respect to a given cancer.

Certain embodiments of the present application include or use one ormore additional therapeutic agent. The one or more additionaltherapeutic agent may be an agent useful for the treatment of cancer,inflammation, autoimmune disease and/or related conditions. The one ormore additional therapeutic agent may be a chemotherapeutic agent, ananti-angiogenic agent, an antifibrotic agent, an anti-inflammatoryagent, an immune modulating agent, an immunotherapeutic agent, atherapeutic antibody, a radiotherapeutic agent, an anti-neoplasticagent, an anti-cancer agent, an anti-proliferation agent, or anycombination thereof. In some embodiments, the compound(s) describedherein may be used or combined with a chemotherapeutic agent, ananti-angiogenic agent, an anti-fibrotic agent, an anti-inflammatoryagent, an immune modulating agent, an immunotherapeutic agent, atherapeutic antibody, a radiotherapeutic agent, an antineoplastic agentor an anti-cancer agent, an anti-proliferation agent, or any combinationthereof.

In one embodiment, a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof optionally incombination with an additional anticancer agent described herein, may beused or combined with an anti-neoplastic agent or an anti-cancer agent,anti-fibrotic agent, an anti-anti-inflammatory agent, or an immunemodulating agent.

In one embodiment, provided are kits comprising a pharmaceuticalcomposition comprising a compound of Formula (I), Formula (Ia), Formula(II), or Formula (IIa) or a tautomer or pharmaceutically acceptable saltthereof, and at least one additional anticancer agent, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. In one embodiment, provided arekits comprising a pharmaceutical composition comprising a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula(IV), or Formula (IVa), or a tautomer or pharmaceutically acceptablesalt thereof, and at least one additional anticancer agent, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. In one embodiment, the kitcomprises instructions for use in the treatment of cancer. In oneembodiment, the instructions in the kit are directed to use of thepharmaceutical composition for the treatment of a hematologicmalignancy, multiple myeloma, breast cancer, colorectal cancer, skincancer, melanoma, ovarian cancer, kidney cancer, small cell lung cancer,non-small cell lung cancer, lymphoma, and/or leukemia.

The application also provides method for treating a subject who isundergoing one or more standard therapies, such as chemotherapy,radiotherapy, immunotherapy, surgery, or combination thereof comprisingadministering or co-administering a compound of Formula (I), Formula(Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa),Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula(IVa), or a tautomer or pharmaceutically acceptable salt thereof to saidsubject. Accordingly, one or more compound(s) of Formula (I), Formula(Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa),Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula(IVa), or tautomers or pharmaceutically acceptable salts thereof, may beadministered before, during, or after administration of a chemotherapy,radiotherapy, immunotherapy, surgery or combination thereof.

In one embodiment, the subject may be a human who is (i) substantiallyrefractory to at least one chemotherapy treatment, or (ii) in relapseafter treatment with chemotherapy, or both (i) and (ii). In some ofembodiments, the subject is refractory to at least two, at least three,or at least four chemotherapy treatments (including standard orexperimental chemotherapies).

In one embodiment, the subject is refractory to at least one, at leasttwo, at least three, or at least four chemotherapy treatment (includingstandard or experimental chemotherapy) selected from fludarabine,rituximab, obinutuzumab, alkylating agents, alemtuzumab and otherchemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin,vincristine, prednisone); R—CHOP (rituximab-CHOP); hyperCVAD(hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, cytarabine); R-hyperCVAD(rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide,mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide,mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab;temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP;CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP);ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR(fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab);and D.T. PACE (dexamethasone, thalidomide, cisplatin, Adriamycin®,cyclophosphamide, etoposide).

Other examples of chemotherapy treatments (including standard orexperimental chemotherapies) are described below. In addition, treatmentof certain lymphomas is reviewed in Cheson, B. D., Leonard, J. P.,“Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma” The NewEngland Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W. G.,“Current and Investigational Therapies for Patients with CLL” Hematology2006, p. 285-294. Lymphoma incidence patterns in the United States areprofiled in Morton, L. M., et al. “Lymphoma Incidence Patterns by WHOSubtype in the United States, 1992-2001” Blood 2006, 107(1), p. 265-276.

Examples of immunotherapeutic agents treating lymphoma or leukemiainclude, but are not limited to, rituximab (such as Rituxan),alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies,anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab,CHIR-12.12, epratuzumab (hLL2-anti-CD22 humanized antibody), galiximab,ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab,PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptidevaccine, tositumomab, autologous human tumor-derived HSPPC-96, andveltuzumab. Additional immunotherapy agents include using cancervaccines based upon the genetic makeup of an individual patient's tumor,such as lymphoma vaccine example is GTOP-99 (MyVax®).

Examples of chemotherapy agents for treating lymphoma or leukemiainclude aldesleukin, alvocidib, antineoplaston AS2-1, antineoplastonA10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin,arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263,BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin,campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine,cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin,cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin),cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel,dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicinhydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus(RAD001), fenretinide, fdgrastim, melphalan, mesna, Flavopiridol,Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecanhydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013),lymphokine-activated killer cells, melphalan, methotrexate, mitoxantronehydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine,oblimersen (Genasense) Obatoclax (GX15-070), oblimersen, octreotideacetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991,PEGylated liposomal doxorubicin hydrochloride, pegfdgrastim, Pentstatin(Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine(Selicilib, CYC202), recombinant interferon alfa, recombinantinterleukin-12, recombinant interleukin-11, recombinant flt3 ligand,recombinant human thrombopoietin, rituximab, sargramostim, sildenafdcitrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus,tanespimycin, Temsirolimus (CCl-779), Thalidomide, therapeuticallogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib orPS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbineditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine,rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine,prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM(fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine,cyclophosphamide, rituximab), hyperCVAD (hyperfractionatedcyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate,cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP(mitoxantrone, chlorambucil, and prednisolone), R—CHOP (rituximab plusCHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE(rituximab-ICE), and R-MCP (Rituximab-MCP).

In some embodiments, the cancer is melanoma. Suitable agents for use incombination with the compounds described herein include, withoutlimitation, dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC,temozolomide or YERVOY™. Compounds disclosed herein may also be combinedwith immunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in the treatment ofmelanoma.

Compounds described here may also be used in combination with vaccinetherapy in the treatment of melanoma. Anti-melanoma vaccines are, insome ways, similar to the anti-virus vaccines which are used to preventdiseases caused by viruses such as polio, measles, and mumps. Weakenedmelanoma cells or parts of melanoma cells called antigens may beinjected into a patient to stimulate the body's immune system to destroymelanoma cells.

Melanomas that are confined to the arms or legs may also be treated witha combination of agents including one or more compounds describedherein, using for example, a hyperthermic isolated limb perfusiontechnique. This treatment protocol temporarily separates the circulationof the involved limb from the rest of the body and injects high doses ofchemotherapy into the artery feeding the limb, thus providing high dosesto the area of the tumor without exposing internal organs to these dosesthat might otherwise cause severe side effects. Usually the fluid iswarmed to 102° to 104° F. Melphalan is the drug most often used in thischemotherapy procedure. This can be given with another agent calledtumor necrosis factor (TNF) and optionally in combination with acompound of Formula (I), Formula (Ia), Formula (II), Formula (IIa),Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula(IIId), Formula (IV), or Formula (IVa).

The therapeutic treatments can be supplemented or combined with any ofthe aforementioned therapies with stem cell transplantation ortreatment. One example of modified approach is radioimmunotherapy,wherein a monoclonal antibody is combined with a radioisotope particle,such as indium In 111, yttrium Y 90, iodine 1-131. Examples ofcombination therapies include, but are not limited to, Iodine-131tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®),Bexxar® with CHOP.

Other therapeutic procedures useful in combination with treatment with acompound of Formula (I), Formula (Ia), Formula (II), Formula (IIa),Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula(IIId), Formula (IV), or Formula (IVa), or a tautomer orpharmaceutically acceptable salt thereof include peripheral blood stemcell transplantation, autologous hematopoietic stem celltransplantation, autologous bone marrow transplantation, antibodytherapy, biological therapy, enzyme inhibitor therapy, total bodyirradiation, infusion of stem cells, bone marrow ablation with stem cellsupport, in vitro-treated peripheral blood stem cell transplantation,umbilical cord blood transplantation, immunoenzyme technique,pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin,conventional surgery, radiation therapy, and nonmyeloablative allogeneichematopoietic stem cell transplantation.

In some embodiments, the present disclosure provides pharmaceuticalcompositions comprising a compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof in combination withan MMP9 binding protein and/or one or more additional therapeutic agent,and a pharmaceutically acceptable diluent, carrier or excipient. In oneembodiment, the pharmaceutical compositions comprise an MMP9 bindingprotein, one or more additional therapeutic agent, and apharmaceutically acceptable excipient, carrier or diluent. In someembodiments, the pharmaceutical compositions comprise the compound offormula (I) and anti-MMP9 antibody AB0045.

In one embodiment, the pharmaceutical compositions comprise the compoundof Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula(III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId),Formula (IV), or Formula (IVa), or a tautomer or pharmaceuticallyacceptable salt thereof, anti-MMP9 antibody AB0045, at least oneadditional therapeutic agent that is an immunomodulating agent, and apharmaceutically acceptable diluent, carrier or excipient. In certainother embodiments, the pharmaceutical compositions comprise theanti-MMP9 antibody AB0045, at least one additional therapeutic agentthat is an anti-inflammatory agent, and a pharmaceutically acceptablediluent, carrier or excipient. In certain other embodiments, thepharmaceutical compositions comprise compound of Formula (I), Formula(Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa),Formula (IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula(IVa), or a tautomer or pharmaceutically acceptable salt thereof, theanti-MMP9 antibody AB0045, at least one additional therapeutic agentthat is an antineoplastic agent or anti-cancer agent, and apharmaceutically acceptable diluent, carrier or excipient. In oneembodiment, MMP9 compounds useful for combination treatment with acompound of Formula (I), Formula (Ia), Formula (II), Formula (IIa),Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula(IIId), Formula (IV), or Formula (IVa), or a tautomer orpharmaceutically acceptable salt thereof, include but are not limited tomarimastat (BB-2516), cipemastat (Ro 32-3555), and those described in WO2012/027721 (Gilead Biologies).

In one embodiment, the one or more additional therapeutic agent is animmune modulating agent, e.g., an immunostimulant or animmunosuppressant. In certain other embodiments, an immune modulatingagent is an agent capable of altering the function of immunecheckpoints, including the CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR,A2aR, CD200 and/or PD-1 pathways. In other embodiments, the immunemodulating agent is immune checkpoint modulating agents. Exemplaryimmune checkpoint modulating agents include anti-CTLA-4 antibody (e.g.,ipilimumab), anti-LAG-3 antibody, anti-B7-H3 antibody, anti-B7-H4antibody, anti-Tim3 antibody, anti-BTLA antibody, anti-KIR antibody,anti-A2aR antibody, anti CD200 antibody, anti-PD-1 antibody, anti-PD-L1antibody, anti-CD28 antibody, anti-CD80 or -CD86 antibody, anti-B7RP1antibody, anti-B7-H3 antibody, anti-HVEM antibody, anti-CD137 or -CD137Lantibody, anti-OX40 or -OX40L antibody, anti-CD40 or -CD40L antibody,anti-GAL9 antibody, anti-IL-10 antibody and A2aR drug. For certain suchimmune pathway gene products, the use of either antagonists or agonistsof such gene products is contemplated, as are small molecule modulatorsof such gene products. In one embodiment, the immune modulatory agent isan anti-PD-1 or anti-PD-L1 antibody. In some embodiments, immunemodulating agents include those agents capable of altering the functionof mediators in cytokine mediated signaling pathways.

In some embodiments, the one or more additional therapy or anti-canceragent is cancer gene therapy or cell therapy. Cancer gene therapy andcell therapy include the insertion of a normal gene into cancer cells toreplace a mutated or altered gene; genetic modification to silence amutated gene; genetic approaches to directly kill the cancer cells;including the infusion of immune cells designed to replace most of thepatient's own immune system to enhance the immune response to cancercells, or activate the patient's own immune system (T cells or NaturalKiller cells) to kill cancer cells, or find and kill the cancer cells;genetic approaches to modify cellular activity to further alterendogenous immune responsiveness against cancer. Non limiting examplesare Algenpantucel-L (2 pancreatic cell lines), Sipuleucel-T, SGT-53liposomal nanodelivery (scL) of gene p53; T-cell therapy, such as CD19CAR-T tisagenlecleucel-T (CTL019) WO2012079000, WO2017049166,axicabtagene ciloleucel (KTE-C19) U.S. Pat. Nos. 7,741,465, 6,319,494,JCAR-015 U.S. Pat. No. 7,446,190, JCAR-014, JCAR-020, JCAR-024,JCAR-023, JTCR-016, JCAR-018 WO2016090190, JCAR-017, (WO2016196388,WO2016033570, WO2015157386), BPX-501 U.S. Pat. No. 9,089,520,WO2016100236, AU-105, UCART-22, ACTR-087, P-BCMA-101; activatedallogeneic natural killer cells CNDO-109-AANK, FATE-NK100, and LFU-835hematopoietic stem cells.

In one embodiment, the one or more additional therapeutic agent is animmune checkpoint inhibitor. Tumors subvert the immune system by takingadvantage of a mechanism known as T-cell exhaustion, which results fromchronic exposure to antigens and is characterized by the up-regulationof inhibitory receptors. These inhibitory receptors serve as immunecheckpoints in order to prevent uncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulator. They act as molecular determinants to influence whether cellcycle progression and other intracellular signaling processes shouldproceed based upon extracellular information.

In addition to specific antigen recognition through the T-cell receptor(TCR), T-cell activation is regulated through a balance of positive andnegative signals provided by costimulatory receptors. These surfaceproteins are typically members of either the TNF receptor or B7superfamilies. Agonistic antibodies directed against activatingco-stimulatory molecules and blocking antibodies against negativeco-stimulatory molecules may enhance T-cell stimulation to promote tumordestruction.

Programmed Cell Death Protein 1, (PD-1 or CD279), a 55-kD type 1transmembrane protein, is a member of the CD28 family of T cellco-stimulatory receptors that include immunoglobulin superfamily memberCD28, CTLA-4, inducible co-stimulator (ICOS), and BTLA. PD-1 is highlyexpressed on activated T cells and B cells. PD-1 expression can also bedetected on memory T-cell subsets with variable levels of expression.Two ligands specific for PD-1 have been identified: programmeddeath-ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (alsoknown as B7-DC or CD273). PD-L1 and PD-L2 have been shown todown-regulate T cell activation upon binding to PD-1 in both mouse andhuman systems (Okazaki et al., Int. Immunol., 2007; 19: 813-824). Theinteraction of PD-1 with its ligands, PD-L1 and PD-L2, which areexpressed on antigen-presenting, cells (APCs) and dendritic cells (DCs),transmits negative regulatory stimuli to down-modulate the activated Tcell immune response. Blockade of PD-1 suppresses this negative signaland amplifies T cell responses. Numerous studies indicate that thecancer microenvironment manipulates the PD-L1/PD-1 signaling pathway andthat induction of PD-L1 expression is associated with inhibition ofimmune responses against cancer, thus permitting cancer progression andmetastasis. The PD-L1/PD-1 signaling pathway is a primary mechanism ofcancer immune evasion for several reasons. This pathway is involved innegative regulation of immune responses of activated T effector cellsfound in the periphery. PD-L1 is up-regulated in cancermicroenvironments, while PD-1 is also up-regulated on activated tumorinfiltrating T cells, thus possibly potentiating a vicious cycle ofinhibition. This pathway is also intricately involved in both innate andadaptive immune regulation through bi-directional signaling. Thesefactors make the PD-1/PD-L1 complex a central point through which cancercan manipulate immune responses and promote its own progression.

The first immune-checkpoint inhibitor to be tested in a clinical trialwas ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 mAh. CTLA-4belongs to the immunoglobulin superfamily of receptors, which alsoincludes PD-1, BTLA, TIM-3, and V-domain immunoglobulin suppressor of Tcell activation (VISTA). Anti-CTLA-4 mAh is a powerful checkpointinhibitor which removes “the break” from both naive andantigen-experienced cells.

Therapy enhances the antitumor function of CD8+ T cells, increases theratio of CD8+ T cells to Foxp3+ T regulatory cells, and inhibits thesuppressive function of T regulatory cells. TIM-3 has been identified asanother important inhibitory receptor expressed by exhausted CD8+ Tcells. In mouse models of cancer, it has been shown that the mostdysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1and LAG-3. LAG-3 is another recently identified inhibitory receptor thatacts to limit effector T-cell function and augment the suppressiveactivity of T regulatory cells. It has recently been revealed that PD-1and LAG-3 are extensively co-expressed by tumor-infiltrating T cells inmice, and that combined blockade of PD-1 and LAG-3 provokes potentsynergistic antitumor immune responses in mouse models of cancer.

Thus in one embodiment, the present disclosure provides the use of acompound of Formula (I), Formula (Ia), Formula (II), Formula (IIa),Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula(IIId), Formula (IV), or Formula (IVa), or a tautomer orpharmaceutically acceptable salt thereof in combination with one or moreadditional immune checkpoint inhibitors. In one embodiment, the presentdisclosure provides the use of a compound of Formula (I), Formula (Ia),Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula(IIIb), Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa),or a tautomer or pharmaceutically acceptable salt thereof, with one ormore immune checkpoint inhibitors and an anti-MMP9 antibody or antigenbinding fragment thereof to treat or prevent cancer. In someembodiments, the immune checkpoint inhibitors may be an anti-PD-1 and/oran anti-PD-L1 antibody or an anti PD-1/PD-L1 interaction inhibitor. Insome embodiments, the anti-PD-L1 antibody may be B7-H1 antibody, BMS936559 antibody, MPDL3280A (atezolizumab) antibody, MEDI-4736 antibody,MSB0010718C antibody or combinations thereof. According to anotherembodiment, the anti-PD-1 antibody may be nivolumab antibody,pembrolizumab antibody, pidilizumab antibody or combinations thereof.

In addition, PD-1 may also be targeted with AMP-224, which is aPD-L2-IgG recombinant fusion protein. Additional antagonists ofinhibitory pathways in the immune response include IMP321, a solubleLAG-3 Ig fusion protein and MHC class II agonist, which is used toincrease an immune response to tumors. Lirilumab is an antagonist to theKIR receptor and BMS 986016 is an antagonist of LAG3. TheTIM-3-Galectin-9 pathway is another inhibitory checkpoint pathway thatis also a promising target for checkpoint inhibition. RX518 targets andactivates the glucocorticoid-induced tumor necrosis factor receptor(GITR), a member of the TNF receptor superfamily that is expressed onthe surface of multiple types of immune cells, including regulatory Tcells, effector T cells, B cells, natural killer (NK) cells, andactivated dendritic cells. Thus, in one embodiment, a compound ofFormula (I), or a tautomer or pharmaceutically acceptable salt thereof,is used in combination with IMP321, Lirilumab and/or BMS 986016.

Anti-PD-1 antibodies that may be used in the compositions and methodsdescribed herein include but are not limited to:Nivolumab/MDX-1106/BMS-936558/ONO1152, a fully human lgG4 anti-PD-1monoclonal antibody; pidilizumab (MDV9300/CT-011), a humanized lgG1monoclonal antibody; pembrolizumab(MK-3475/pembrolizumab/lambrolizumab), a humanized monoclonal IgG4antibody; durvalumab (MEDI-4736) and atezolizumab. Anti-PD-L1 antibodiesthat may be used in compositions and methods described herein includebut are not limited to: avelumab; BMS-936559, a fully human IgG4antibody; atezolizumab (MPDL3280A/RG-7446), a human monoclonal antibody;MEDI4736; MSB0010718C, and MDX1105-01.

In one embodiment, the compound of Formula (I), Formula (Ia), Formula(II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IIIb),Formula (IIIc), Formula (IIId), Formula (IV), or Formula (IVa), or atautomer or pharmaceutically acceptable salt thereof, is administered incombination with the anti-PD-1 antibody nivolumab, pembrolizumab, and/orpidilizumab to a patient in need thereof. In one embodiment, theanti-PD-L1 antibody useful for combination treatment with a compound ofFormula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III),Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId), Formula(IV), or Formula (IVa), or a tautomer or pharmaceutically acceptablesalt thereof, is BMS-936559, atezolizumab, or avelumab. In oneembodiment, the immune modulating agent inhibits an immune checkpointpathway. In another embodiment, the immune checkpoint pathway isselected from CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200and PD-1. Additional antibodies that may be used in combination with acompound of Formula (I), Formula (Ia), Formula (II), Formula (IIa),Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula(IIId), Formula (IV), or Formula (IVa), or a tautomer orpharmaceutically acceptable salt thereof, in compositions and methodsdescribed herein include the anti-PD-1 and anti-PD-L1 antibodiesdisclosed in U.S. Pat. Nos. 8,008,449 and 7,943,743, respectively.

In one embodiment, the one or more additional therapeutic agent is ananti-inflammatory agent. In certain other embodiments, theanti-inflammatory agent is a tumor necrosis factor alpha (TNF-α)inhibitor. As used herein, the terms “TNF alpha,” “TNF-α,” and “TNFα,”are interchangeable. TNF-α is a pro-inflammatory cytokine secretedprimarily by macrophages but also by a variety of other cell typesincluding lymphoid cells, mast cells, endothelial cells, cardiacmyocytes, adipose tissue, fibroblasts, and neuronal tissue. TNF-α isalso known as endotoxin-induced factor in serum, cachectin, anddifferentiation inducing factor. The tumor necrosis factor (TNF) familyincludes TNF alpha, TNF beta, CD40 ligand (CD40L), Fas ligand (FasL),TNF-related apoptosis inducing ligand (TRAIL), and LIGHT (homologous tolymphotoxins, exhibits inducible expression, and competes with HSVglycoprotein D for HVEM, a receptor expressed by T lymphocytes), some ofthe most important cytokines involved in, among other physiologicalprocesses, systematic inflammation, tumor lysis, apoptosis andinitiation of the acute phase reaction.

The above therapeutic agents when employed in combination with acompound(s) disclosed herein, may be used, for example, in those amountsindicated in the referenced manuals e.g., Physicians Desk Reference orin amounts generally known to a qualified care giver, i.e., one ofordinary skill in the art. In the methods of the present disclosure,such other therapeutic agent(s) may be administered prior to,simultaneously with, or following the administration of the compound(s)of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula(III), Formula (IIIa), Formula (IIIb), Formula (IIIc), Formula (IIId),Formula (IV), or Formula (IVa), or a tautomer or pharmaceuticallyacceptable salt thereof. Certain other therapeutic agents may becombined into a single formulation or kit when amenable to such. Forexample, tablet, capsule or liquid formulations may be combined withother tablet, capsule or liquid formulations into one fixed or combineddose formulation or regimen. Other combinations may be given separately,contemporaneously or otherwise.

Compound Preparation

Some embodiments of the instant disclosure are directed to processes andintermediates useful for preparing the subject compounds orpharmaceutically acceptable salts thereof.

Compounds described herein can be purified by any of the means known inthe art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 4^(th) ed., Wiley, New York 2006. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

General Synthetic Schemes Scheme 1: Preparation of Optically PureCompounds of Formula (I)

Intermediates A and E can be prepared using procedures described inInternational Publication No. WO 2016/033486.

Step 1

Intermediate B can be prepared by treating a solution of A in anappropriate solvent, for example THF, with an appropriate base such assodium hydride, and then treating with an appropriate alkylating agentsuch as iodomethane.

Step 2

Intermediate C can be prepared by treating a solution of B in anappropriate solvent, for example DMF, with an appropriate base such assodium hydride, and then treating the mixture with an appropriatealkylating agent such as iodomethane.

Step 3

Intermediate D can be prepared by treating Intermediate C with anappropriate base, such as aqueous NaOH, KOH or LiOH, in appropriatesolvent, for example MeOH, EtOH or THF, at elevated temperature,preferably 60° C. overnight. After cooling the mixture, acidifying withan appropriate acidic agent such as HCl, concentrating, and filtering,the resulting solid carboxylic acid is dissolved in an appropriatesolvent, such as CH₂Cl₂ or 1,2-dichloroethane. An appropriate acidchloride forming agent, for example thionyl chloride or oxalyl chloride,can be added to provide Intermediate D, which can be used immediately inthe next step.

Step 4

Intermediate F can be prepared by dissolving Intermediate E in anappropriate solvent such as THF, DMF or CH₂Cl₂, treating with anappropriate organic base, such as trimethylamine, diisopropylethylamineor imidazole, and an appropriate silylating agent, such as TBDMSCl orTBDMSOTf, at appropriate temperature, preferably at 0° C.

Step 5

Intermediate G can be prepared by suspending Ph₃PCl₂ in an appropriatesolvent, such as CH₂Cl₂ or 1,2-dichloroethane, under a N₂ atmosphere,adding an appropriate organic base, such as trimethylamine ordiisopropylethylamine, and then adding a solution of Intermediate F inan appropriate solvent such as CH₂Cl₂ or 1,2-dichloroethane followed bybubbling ammonia gas.

Step 6

Intermediate H can be prepared by dissolving Intermediate D in anappropriate polar solvent, such as acetonitrile, and adding pyridazine,followed by Intermediate G in an appropriate polar solvent such asacetonitrile.

Step 7

Intermediates 1-1 and 1-2 can be prepared by adding triethylamine andacid chloride under ice-bath cooling to a solution of Intermediate H inan appropriate solvent such as CH₂Cl₂ or 1,2-dichloroethane. The twostereoisomers can be separated during purification.

Steps 8 and 9

J-1 and J-2 can be prepared by stirring the Intermediate 1-1 or 1-2,respectively, with Hoveyda Grubbs 2^(nd) generation catalyst in anappropriate solvent such as CH₂Cl₂ or 1,2-dichloroethane at elevatedtemperature, preferably 60° C. After concentration, the residue can bepurified by prep-HPLC or by silica gel column chromatography.

Scheme 2: Preparation of Optically Pure Compounds of Formula (I)

J-1 and J-2 can also be prepared from H as shown in Scheme 2. A solutionof Intermediate H in an appropriate solvent, such as CH₂Cl₂ or1,2-dichloroethane, can be treated with di-tert-butyl dicarbonate underice bath cooling in the presence of appropriate base such as DIPEA orTEA, and stirring at rt overnight. After concentration and purificationby silica gel chromatography, the mixture of Boc protected diastereomerscan be treated with Hoveyda Grubbs 2^(nd) generation catalyst in anappropriate solvent, such as CH₂Cl₂ or 1,2-dichloroethane, at elevatedtemperature, preferably at 60° C. After concentration, the mixture ofdiastereomers L can be acylated with an appropriate acylating agent,such acid chloride and an organic base, or carboxylic acid with EDCI andan organic base.

Scheme 3: Preparation of Optically Pure Compounds of Formula (I)

J-1 and J-2 can also be separated by either silica gel columnchromatography or by chiral HPLC after acylation of Intermediate H andmacrocyclization of Intermediate I with Hoveyda Grubbs 2^(nd) generationcatalyst.

Scheme 4: Preparation of Optically Pure Compounds of Formula (I)

Step 1

Intermediates K-1 and K-2 can be prepared by adding triethylamine anddi-tert-butyl dicarbonate to a solution of Intermediate H in anappropriate solvent, such as CH₂Cl₂ or 1,2-dichloroethane, under icebath cooling, and stirring the mixture at rt overnight. Afterconcentrating the reaction mixture, the residue can be purified byprep-HPLC or silica gel column chromatography to separate thediastereomers.

Steps 2 and 3

J-1 and J-2 can be prepared by stirring Intermediate K-1 or K-2 andHoveyda Grubbs 2^(nd) generation catalyst in an appropriate solvent,such as CH₂Cl₂ or 1,2-dichloroethane, at elevated temperature,preferably at 60° C. After concentrating the reaction mixture andpurifying the residue by prep-HPLC, an appropriate acylating agent, suchacid chloride and an organic base, or carboxylic acid with EDCI and anorganic base, are added to acylate Intermediate L-1 or L-2, which can bepurified by prep-HPLC or by silica gel column chromatography to affordJ-1 or J-2.

Scheme 5: Preparation of Optically Pure Compounds of Formula (I)

Intermediates L-1 and L-2 can be separated by either silica gel columnchromatography or by chiral HPLC after Boc protection andmacrocyclization with Hoveyda Grubbs 2^(nd) generation catalyst, andthen acylated to provide J-1 and J-2 respectively.

Scheme 6: Preparation of Optically Pure Compounds of Formula (I)

N-1 and N-2 can be prepared from L as shown in Scheme 6, separated byeither silica gel column chromatography or by chiral HPLC afteracylation followed by macrocyclization with Hoveyda Grubbs 2^(nd)generation catalyst.

Schemes 7 and 8: Preparation of Compounds of Formula (I) Wherein —C(O)R¹is —C(O)NHR⁸

M-2 can be prepared from L-2 by adding triethylamine and substitutedisocyanate in an appropriate solvent such as CH₂Cl₂ or1,2-dichloroethane under ice-bath cooling.

Alternatively, the two stereoisomers M-1 and M-2 can be separated byeither silica gel column chromatography or by chiral HPLC after treatingL-2 with substituted isocyanate in an appropriate solvent such as CH₂Cl₂or 1,2-dichloroethane in the presence of appropriate base such astriethylamine.

Scheme 9: Preparation of Compounds of Formula (I) Wherein —C(O)R¹ is—C(O)NR⁸R⁹

M-3 can be prepared by treating L-2 with diphenyl carbonate followed byan appropriate amine (Scheme 9).

Schemes 10, 11, and 12: Preparation of Compounds of Formula (I) Wherein—C(O)R¹ is —C(O)OR⁷

O-2 can be prepared by treating L-2 with an appropriate chlorocarbonateand an appropriate base such as trimethylamine in an appropriate solventsuch as CH₂Cl₂ or 1,2-dichloroethane.

Alternatively, O-2 can be prepared by treating L-2 with diphenylcarbonate followed by an appropriate alcohol.

Alternatively, two stereoisomers can be separated by either silica gelcolumn chromatography or by chiral HPLC after treating diastereomericmixture L with diphenyl carbonate followed by an appropriate alcohol asthe nucleophile or with substituted chloroformate, under ice-bathcooling to afford O-2 (Scheme 12).

EXAMPLES

Exemplary chemical entities of the present disclosure are provided inthe specific examples that follow. Those skilled in the art willrecognize that, to obtain the various compounds herein, startingmaterials may be suitably selected so that the ultimately desiredsubstituents will be carried through the reaction scheme with or withoutprotection as appropriate to yield the desired product. Alternatively,it may be necessary or desirable to employ, in the place of theultimately desired substituent, a suitable group that may be carriedthrough the reaction scheme and replaced as appropriate with the desiredsubstituent. Furthermore, one of skill in the art will recognize thatthe transformations shown in the schemes below may be performed in anyorder that is compatible with the functionality of the particularpendant groups.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

Example 1

Step 1: Preparation of methyl(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(1-1)

To a stirred solution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylicacid (prepared according to procedure described in International PatentApplication No. WO 2016/033486) (1.02 g, 2.18 mmol) in THF (10 mL) wasadded sodium hydride (60% in mineral oil, 183.1 mg, 4.57 mmol) in an icebath, followed by iodomethane (618.7 mg, 4.359 mmol). The resultingmixture was stirred at rt for 5 h. The reaction mixture was then pouredinto ice cold H₂O and extracted with CH₂Cl₂. The organic layer wasconcentrated and purified by silica gel column (EtOAc/Hexanes=2/3) toafford methyl(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate.LCMS-ESI+: (m/z): [M+H]+ calcd for C₂₈H₃₂ClNO₄: 482.0; found: 482.2.

Step 2: Preparation of methyl(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(1-2)

To a stirred solution of methyl(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate(707.0 mg, 1.4 mmol) in DMF (8 mL) was added sodium hydride (60% inmineral oil, 88.0 mg, 2.2 mmol) in an ice bath, followed by iodomethane(312.3 mg, 2.2 mmol). The resulting mixture was stirred at rt overnight.The reaction mixture was then poured into ice cold H₂O and extractedwith CH₂Cl₂. The organic layer was concentrated and purified by silicagel column (EtOAc/Hexanes=1/4) to afford methyl(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate. LCMS-ESI+: (m/z): [M+H]+calcd for C₂₉H₃₄ClNO₄: 496.0; found: 496.2.

Step 3: Preparation of (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonylchloride (1-3)

Methyl(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (659.0 mg, 1.33 mmol) wasstirred in 2N aq NaOH (3 mL) and MeOH (8 mL) at 60° C. overnight. Aftercooling, the mixture was acidified with HCl and concentrated. Theresulting solid was treated with CH₂Cl₂ and filtered. The filtrate wasconcentrated, and 174.5 mg (0.36 mmol) was dissolved in CH₂Cl₂ (6 mL).Thionyl chloride (1.5 mL) was added to the solution in an ice bath. Theresulting mixture was stirred at rt for 2 h and concentrated. Crude(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonylchloride was used directly in the next step.

Step 4: Preparation of(2R,3S)—N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide(1-4)

To a stirred solution of (2R,3S)-3-methylhex-5-ene-2-sulfonamide (2.00g, 11.28 mmol) in THF (16 mL) was added triethylamine (3.15 mL, 22.57mmol) in an ice bath, followed by TBDMSCl (2.13 g, 14.10 mmol) in THF (8mL) slowly. The resulting mixture was stirred at rt for 2 days. Theprecipitate was filtered and washed with ether. The filtrate wasconcentrated and purified by silica gel column (EtOAc/Hexanes=1/4) toafford(2R,3S)—N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide. ¹HNMR (400 MHz, Chloroform-d) δ 5.76-5.67 (m, 1H), 5.08-5.02 (m, 2H), 3.95(s, 1H), 3.95-2.97 (m, 1H), 2.44-2.41 (m, 1H), 2.14-2.08 (m, 1H),2.02-1.96 (m, 1H), 1.27 (d, J=8.0 Hz, 3H), 1.02 (d, J=8.0 Hz, 3H), 0.94(m, 9H), 0.27-0.26 (m, 6H).

Step 5: Preparation of(2R,3S)—N′-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonimidamide(1-5)

To a stirred suspension of Ph₃PCh (754.33 mg, 2.264 mmol) in CH₂Cl₂ (4.0mL) under a N₂ atmosphere, was added trimethylamine (0.43 mL, 3.087mmol). The mixture was stirred for 10 min at rt, then cooled to 0° C.,and a solution of(2R,3S)—N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide(600.00 mg, 2.058 mmol) in CH₂Cl₂ (4 mL) was added. The reaction mixturewas stirred for 1 h at 0° C. Ammonia gas was bubbled in the reactionmixture. The reaction vessel was sealed, stirred at 0° C. for 2 h. Theresulting precipitate was filtered and washed with CH₂Cl₂. The filtratewas concentrated and purified by silica gel column (EtOAc/Hexanes=1/4)to afford(2R,3S)—N′-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonimidamide(1-5). ¹H NMR (400 MHz, Chloroform-d) δ 5.80-5.69 (m, 1H), 5.08-5.02 (m,2H), 4.17 (w, 2H), 3.06-2.98 (m, 1H), 2.54-2.46 (m, 1H), 2.11-1.95 (m,2H), 1.29-1.26 (m, 3H), 1.01-0.98 (m, 3H), 0.92-0.88 (m, 9H), 0.13-0.11(m, 6H).

Step 6: Preparation of(3S)—N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide(1-6)

To a stirred solution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl chloride (181.00 mg, 0.362 mmol)in acetonitrile (2.0 mL) was added pyridazine (0.03 mL, 0.362 mmol)) in2 mL of acetonitrile, followed by(2R,3S)—N′-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonimidamide(126.00 mg, 0.434 mmol) in acetonitrile solution (2.0 mL). The resultingmixture was stirred at rt for 3 h. After concentration the residue waspurified by silica gel column (EtOAc/Hexanes=2/3) to afford(3S)—N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide.¹H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J=11.6 Hz, 1H), 7.62-7.58 (m,2H), 7.15 (d, J=8.8 Hz, 1H), 7.10-7.07 (m, 1H), 6.95 (d, J=8.4 Hz, 1H),5.80-5.49 (m, 2H), 5.18-5.02 (m, 4H), 4.15 (dd, J=12.0, 5.2 Hz, 1H),4.05 (dd, J=12.0, 4.4 Hz, 1H), 3.71-3.61 (m, 2H), 3.49-3.28 (m, 3H),3.25-3.24 (m, 3H), 2.81-2.45 (m, 5H), 2.15-1.52 (m, 10H), 1.40 (dd,J=12.8, 6.8 Hz, 3H), 1.09 (dd, J=28.4, 6.8 Hz, 3H). LCMS-ESI+: (m/z):[M+H]+ calcd for C₃₅H₄₆ClN₃O₄S: 640.3; found: 640.3.

Step 7: Preparation of 1-7 and 1-8

To a stirred solution of(3S)—N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide (30.00 mg, 0.047 mmol) inCH₂Cl₂ (4.0 mL) was added triethylamine (0.01 mL, 0.07 mmol) in an icebath, followed by propionyl chloride (5.20 mg, 0.056 mmol). Theresulting mixture was stirred at rt for 2 h. After concentration, theresidue was purified by preparative HPLC (Phenomenex Luna 5 μm C18 (2),150×21.2 mm, 50% to 90-95% acetonitrile/water with 0.1% trifluoroaceticacid, 15 mL/min, used throughout this experimental section unlessotherwise mentioned) to afford the 1-7 (more polar fraction) and 1-8(less polar fraction). LCMS-ESI+: (m/z): [M+H]+ calcd for C₃₈H₅₀ClN₃O₅S:696.3; found: 696.3.

Step 8: Preparation of Example 1

The single diastereomer 1-7 from step 7 (11.0 mg, 0.016 mmol) andHoveyda Grubbs generation 2 catalyst (2.0 mg, 0.003 mmol) were stirredin 1,2-dichloroethane (6.0 mL) at 60° C. for 4 h. After concentration,the residue was purified by preparative HPLC to afford Example 1. ¹H NMR(400 MHz, Chloroform-d) δ 7.72 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.2, 1.8Hz, 1H), 7.19-7.16 (m, 2H), 7.08 (d, J=2.4 Hz, 1H), 6.88 (d, J=8.0 Hz,1H), 5.86-5.80 (m, 1H), 5.69 (dd, J=15.8, 7.4 Hz, 1H), 4.30-4.26 (m,1H), 4.05 (dd, J=22.8, 12.0 Hz, 2H), 3.80-3.72 (m, 3H), 3.37 (d, J=14.4Hz, 1H), 3.27 (s, 3H), 3.06 (dd, J=14.8, 10.8 Hz, 1H), 2.85-2.75 (m,3H), 2.58-1.68 (m, 14H), 1.42 (d, J=6.8 Hz, 3H), 1.15 (t, J=7.6 Hz, 3H),1.11 (d, J=6.8 Hz, 3H). LCMS-ESI+: (m/z): [M+H]+ calcd forC₃₆H₄₆ClN₃O₅S: 668.3; found: 668.3.

Example 2

Example 2 was synthesized in the same manner as Example 1 (Step 8) usingdiastereomer 1-8 instead of 1-7. ¹H NMR (400 MHz, Chloroform-d) δ 7.70(d, J=8.8 Hz, 1H), 7.18 (dd, J=8.4, 2.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H),7.08 (d, J=2.4 Hz, 1H), 7.02 (s, 1H), 6.94 (d, J=8.0 Hz, 1H), 5.99-5.92(m, 1H), 5.50 (dd, J=15.2, 8.8 Hz, 1H), 4.47 (w, 1H), 4.13-4.04 (m, 2H),3.82 (d, J=15.2 Hz, 1H), 3.71-3.65 (m, 2H), 3.31-3.24 (m, 1H), 3.22 (s,3H), 2.99 (dd, J=15.2, 10.0 Hz, 1H), 2.80-2.70 (m, 3H), 2.49-1.64 (m,13H), 1.54 (d, J=6.8 Hz, 3H), 1.42-1.36 (m, 1H), 1.17 (t, J=7.6 Hz, 3H),1.02 (d, J=6.4 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₆H₄₆ClN₃O₅S:668.3; found: 668.3.

Examples 3 and 4

Step 1: Preparation ofN′-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide

N′-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide was prepared inthe same manner as Example 1 (step 4 and step 5) usingpent-4-ene-1-sulfonamide instead of(2R,3S)-3-methylhex-5-ene-2-sulfonamide). ¹H NMR (400 MHz, Chloroform-d)δ 5.78 (ddt, J=17.0, 10.2, 6.8 Hz, 1H), 5.09-5.01 (m, 2H), 3.13-3.05 (m,2H), 2.22-2.16 (m, 2H), 1.98-1.90 (m, 2H), 0.90 (s, 9H), 0.12 (s, 3H),0.11 (s, 3H).

Step 2: Preparation of(3S)—N-(amino(oxo)(pent-4-en-1-yl)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide

N′-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide was treatedwith(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonylchloride in the presence of pyridazine in similar manner as in Example 1(step 6) to give the title compound.

Step 3: Preparation of (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N—((R)-oxo(pent-4-en-1-yl)(propionamido)-16-sulfanylidene)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide

To a stirred solution of(3S)—N-(amino(oxo)(pent-4-en-1-yl)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide(66 mg, 0.11 mmol) in CH₂Cl₂ (5.0 mL) was added triethyl amine (0.02 mL,0.162 mmol) in an ice bath, followed by propionyl chloride (11.97 mg,0.129 mmol). The resulting mixture was stirred at rt for 2 h. Afterconcentration, the residue was purified by preparative HPLC to afford(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N—((R)-oxo(pent-4-en-1-yl)(propionamido)-16-sulfanylidene)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide.

Step 4: Preparation of Example 3 and Example 4

(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N—((R)-oxo(pent-4-en-1-yl)(propionamido)-16-sulfanylidene)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide (55.0 mg, 0.082 mmol) andHoveyda Grubbs generation 2 catalyst (5.14 mg, 0.008 mmol) were stirredin 1,2-dichloroethane (16.0 mL) at 60° C. for 4 h. After concentration,the residue was purified by preparative HPLC to afford Example 3 (morepolar fraction) (LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₄H₄₂ClN₃O₅S: 640.2;found: 640.2) and Example 4 (less polar fraction) (¹H NMR (400 MHz,Chloroform-d) δ 7.68 (d, J=9.2 Hz, 1H), 7.37-7.35 (m, 1H), 7.23 (s, 1H),7.08-7.06 (m, 2H), 6.92 (d, J=8.4 Hz, 1H), 5.86-5.82 (m, 1H), 5.74-5.70(m, 1H), 4.06 (d, J=12.0 Hz, 1H), 3.99-3.95 (m, 2H), 3.81-3.71 (m, 4H),3.59-3.57 (m, 1H), 3.34 (d, J=14.8 Hz, 1H), 3.29 (s, 3H), 3.04-2.98 (m,1H), 2.78-2.73 (m, 4H), 2.50 (q, J=7.4 Hz, 2H), 2.38-1.66 (m, 10H),1.39-1.34 (m, 1H), 1.22 (t, J=7.4 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₃₄H₄₂ClN₃O₅S: 640.2; found: 640.2).

Examples 5 and 6

Method 1 Step 1: Preparation of tert-butyl((R)—N—((S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamateand tert-butyl(N—((S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate

To a stirred solution of(3S)—N-(amino(oxo)(pent-4-en-1-yl)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide (Example 3/4 step 2, 32.00 mg,0.052 mmol) in CH₂Cl₂ (5.0 mL) was added triethylamine (0.02 mL, 0.105mmol) in an ice bath, followed by di-tert-butyl dicarbonate (17.11 mg,0.078 mmol). The resulting mixture was stirred at rt overnight. Afterconcentration, the residue was purified by preparative HPLC to affordtert-butyl((R)—N—((S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamatefrom more polar fraction, and tert-butyl(N—((S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamatefrom less polar fraction.

Step 2: Preparation of Example 5

tert-butyl(N—((S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate(14 mg, 0.02 mmol) and Hoveyda Grubbs generation 2 catalyst (1.25 mg,0.002 mmol) were stirred in 1,2-dichloroethane (6.0 mL) at 60° C. for 4h. After concentration, the residue was purified by preparative HPLC toafford Example 5. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₁H₃₈ClN₃O₄S:584.2; found: 584.2.

Step 3: Preparation of Example 6

Example 6 was synthesized in the same manner as Example 5 usingtert-butyl((R)—N—((S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₁H₃₈ClN₃O₄S: 584.2; found: 584.2.

Method 2

Step 1: Preparation of tert-butyl((R)—N—((S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamate

To a stirred solution of(3S)—N-(amino(oxo)(pent-4-en-1-yl)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide(140.00 mg, 0.229 mmol) in CH₂Cl₂ (5.0 mL) was added triethylamine (0.06mL, 0.458 mmol) in an ice bath, followed by di-tert-butyl dicarbonate(74.97 mg, 0.343 mmol). The resulting mixture was stirred at rtovernight. After concentration, the residue was purified by prep-HPLC toafford tert-butyl((R)—N—((S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl)carbamateas a mixture of diastereomers.

Step 2 and Step 3

The Boc protected mixture of diastereomers from Method 2 Step 1 (112.0mg, 0.157 mmol) and Hoveyda Grubbs generation 2 catalyst (9.83 mg, 0.016mmol) were stirred in 1,2-dichloroethane (6.0 mL) at 60° C. for 4 h.After concentration, the residue was purified by preparative HPLC toafford intermediate 5-1 as a mixture of diastereomers, which werepurified by silica gel column chromatography (EtOAc/Hexanes=3/2) to giveExample 5 (less polar fraction) and Example 6 (more polar fraction).

Method 3

Step 1: Preparation of (S)-4-nitrophenyl (1-phenylethyl) carbonate(5-3-1)

The mixture of (1S)-1-(4-phenylphenyl)ethanol (8.7 g, 71.2 mmol) wasdissolved in MeTHF (90 mL) and cooled to 0° C. To this cold stirredsolution was added pyridine (7.1 mL). A solution of4-nitro-phenyl-chloroformate (14.4 g, 71.2 mmol) in MeTHF (60.0 mL) wasthen added dropwise via dropping funnel. After addition, the resultingmixture was removed from the cooling bath and stirred at ambient for 2hrs. TLC showed (1S)-1-(4-phenylphenyl)ethanol has been consumed but4-nitro-phenyl-chloroformate still remained. Additional(1S)-1-(4-phenylphenyl)ethanol (2.6 g, 21.3 mmol) and pyridine (1.0 mL)were added and stirring continued for overnight. The reaction was thenwashed with 1N HCl (2×), brine (2×), dried over sodium sulfate, filteredand concentrated. The residue was then dissolved in DCM and mixed withsilica gel, concentrated to dryness, divided into two runs, purified bynormal phase chromatography (silica gel, 0-20% EtOAc/Hexanes). Desiredfractions were combined and concentrated to give 5-3-1. 1H NMR (400 MHz,Chloroform-d) δ 8.34-8.16 (m, 2H), 7.48-7.31 (m, 7H), 5.84 (q, J=6.6 Hz,1H), 1.70 (d, J=6.6 Hz, 3H).

Step 2

A solution of N′-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide(2.0 g, 7.18 mmol) in THF (100 mL) was cooled to −50° C. 1.6 M n-BuLi inhexanes (9.65 mL, 15.4 mmol) was added dropwise to this cold solution.The newly formed mixture was stirred at −50° C. for 20 min before asolution of (4-nitrophenyl) [(1S)-1-phenylethyl] carbonate in THF (60mL) was added dropwise slowly. The resulting mixture was stirred at −50°C. for 15 min and then switched to ice-water bath and stirred at 0° C.for 3 hrs. The reaction was quenched with ice and extracted with EtOAc(1×). The organic layer was washed with 1N NaOH (3×), brine (1×), driedover sodium sulfate, filtered, concentrated, and purified by normalphase chromatography (silica gel, 0-20% EtOAc/Hexanes). The purificationwas repeated and the desired fractions were combined and concentrated togive a mixture of diastereomers (5-3-2) and (5-3-3). The mixture ofdiastereomers was subsequently separated into single diastereomers bychiral SFC. The first eluted peak was assigned the chirality as depictedin (5-3-2); the second eluted peak was assigned the chirality asdepicted in (5-3-3). ¹H NMR (400 MHz, Chloroform-d) for the mixture ofdiastereomers: δ 7.41-7.29 (m, 5H), 5.84-5.59 (m, 2H), 5.08-4.93 (m,2H), 3.37-3.16 (m, 2H), 2.19-2.07 (m, 2H), 1.83 (h, J=7.3, 6.7 Hz, 2H),1.57 (dq, J=6.6, 1.8 Hz, 3H), 0.91-0.85 (m, 9H), 0.18 (two sets of s,3H), 0.12 (two sets of s, 3H). 1H NMR (400 MHz, Chloroform-d) for(5-3-2): δ 7.39-7.30 (m, 5H), 5.86-5.58 (m, 2H), 5.07-4.93 (m, 2H), 3.28(tq, J=13.9, 7.9, 7.1 Hz, 2H), 2.13 (p, J=7.7, 7.2 Hz, 2H), 1.85 (p,J=7.2 Hz, 2H), 1.57 (dd, J=6.6, 2.2 Hz, 3H), 0.93-0.91 (m, 9H), 0.19(two sets of s, 6H).

Step 3

The solution of intermediate (5-3-2) (858 mg, 2.1 mmol) in THF (24 mL)was treated with 1.0 M tetrabutylammonium fluoride in THF (6.3 mL, 6.3mmol) at rt for 60 min. The reaction was then concentrated and purifiedby normal phase chromatography (silica gel, 0-80% EtOAc/Hexanes) to give5-3-3A. 1H NMR (400 MHz, Chloroform-d) δ 7.45-7.31 (m, 4H), 5.83-5.59(m, 2H), 5.12-4.96 (m, 2H), 3.35-3.21 (m, 2H), 2.28-2.11 (m, 2H),2.01-1.87 (m, 2H), 1.59 (d, J=6.7 Hz, 3H).

Step 4

To the mixture of(3S)-6′-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazepine-3,1′-tetralin]-7-carbonylchloride (215 mg, 0.45 mmol) in DCM (20 mL) at 0° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (152 mg, 0.98 mmol)followed by 4-(dimethylamino)pyridine (120 mg, 0.98 mmol). After stirredfor 5 min, a solution of intermediate (5-3-3A) (159 mg, 0.54 mmol) inDCM (3 mL) was added and the resulting mixture was removed from thecooling bath and stirred at rt overnight. The reaction was furtherdiluted with DCM (30 mL) and washed with 1N HCl (15 mL), saturatedsodium bicarbonate (15 mL) and brine (15 mL), dried over sodium sulfate,filtered, concentrated and purified by normal phase chromatography(silica gel column, 0-80% EtOAc/Hexanes) to give intermediate 5-3-4.LCMS-ESI+ (m/z): [M+H]+ calcd: 761.0, found: 759.9. ¹H NMR (400 MHz,Chloroform-d) δ 7.67 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 7.39-7.28 (m, 6H),7.16 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.91 (d, J=8.2 Hz,1H), 5.86 (p, J=6.3 Hz, 1H), 5.77-5.48 (m, 2H), 5.21-5.08 (m, 2H),5.08-4.96 (m, 2H), 4.14-4.04 (m, 2H), 3.81-3.71 (m, 2H), 3.70-3.48 (m,3H), 3.39-3.13 (m, 5H), 2.84-2.69 (m, 2H), 2.52 (dd, J=10.7, 7.4 Hz,1H), 2.16 (dt, J=13.3, 7.6 Hz, 3H), 2.01-1.74 (m, 7H), 1.70-1.39 (m,7H).

Step 5

The solution intermediate 5-3-4 in DCE (10 mL) was sparged with nitrogenfor 5 min before Hoveyda-Grubbs 2^(nd) generation catalyst (7 mg, 0.011mmol) was added. The newly formed mixture was degassed for another 2minutes and then it was capped and heated at 60° C. for 16 hrs. Thereaction was then cooled to rt, concentrated, purified by normal phasechromatography (silica gel, 0-5% DCM/MeOH (with 2.0 N NH₃)) to giveExample 5 (first eluted peak: LCMS-ESI+ (m/z): [M+H]+ calcd: 584.2;found: 583.4); and the carbamate protected macrocycle intermediate 5-3-5(second eluted peak: LCMS-ESI+ (m/z): [M+H]+ calcd: 732.3; found:730.8).

Step 6

Intermediate 5-3-5 (15.8 mg, 0.022 mmol) was dissolved in DCM (1.0 mL)at 0° C. TFA (1.0 mL) was added to this cold solution. The resultingmixture was stirred at 0° C. for 2 min and then rt for 1 hr. Thereaction was cooled back to 0° C. and basified with 1N NaOH to pH˜8. Themixture was extracted with DCM (2×). Combined organic layers was washedwith brine (1×), dried over sodium sulfate, filtered, concentrated andpurified by Combiflash (silica gel, 0-100% EtOAc/Hexanes) to giveExample 5. LCMS-ESI+ (m/z): [M+H]+ calcd: 584.2; found: 583.3. ¹H NMR(400 MHz, Chloroform-d) for (8): δ 7.73 (d, J=8.6 Hz, 1H), 7.44-7.39 (m,1H), 7.33 (d, J=1.8 Hz, 1H), 7.16 (dd, J=8.5, 2.3 Hz, 1H), 7.06 (d,J=2.3 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.04-5.93 (m, 1H), 5.73-5.61 (m,1H), 4.12-3.94 (m, 2H), 3.88-3.68 (m, 2H), 3.62-3.51 (m, 2H), 3.40-3.17(m, 6H), 3.00 (dd, J=15.0, 11.0 Hz, 1H), 2.82-2.63 (m, 4H), 2.47-2.20(m, 4H), 1.99-1.59 (m, 6H), 1.37 (t, J=13.1 Hz, 1H).

Example 6 was synthesized in the same manner as Example 5 (Method 3-Step3-6) using intermediate 5-3-3 instead of intermediate 5-3-2.

Examples 7 and 8

Example 7 and Example 8 were prepared in similar manner to Example 3 andExample 4 using 2-methoxyacetyl chloride instead of propionyl chloride.

Example 7

LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₄H₄₂ClN₃O₆S: 656.2; found: 656.2.

Example 8

LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₄H₄₂ClN₃O₆S: 656.2; found: 656.2.

Example 9 and 10

Preparation of Example 9 and Example 10

To a stirred solution of intermediate 5-1 (Example 5/6 Method 2, 10.40mg, 0.018 mmol) in CH₂Cl₂ (5.0 mL) was added triethylamine (0.004 mL,0.027 mmol) in an ice bath, followed by ethyl chloroformate (2.32 mg,0.021 mmol). The resulting mixture was stirred at rt for 2 h. Afterconcentration, the residue was purified by preparative HPLC to affordExample 9 (more polar fraction) (LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₄H₄₂ClN₃O₆S: 656.2; found: 656.2) and Example 10 (less polarfraction).

Examples 11 and 12

Step 1: Preparation of Intermediate 11-1

To a stirred solution of intermediate 5-1 (Example 5/6 Method 2, 17.90mg, 0.031 mmol) in EtOAc (5 mL) was added Platinum (IV) oxide (3.48 mg,0.015 mmol). The resulting mixture was stirred at rt under H₂ for 0.5 h.Filtered the reaction mixture through Celite, and washed with EtOAc. Thefiltrate was concentrated. Crude product (18.0 mg) was used directly fornext step.

Step 2: Preparation of Example 11 and Example 12

To a stirred solution of intermediate 11-1 (18.0 mg, 0.031 mmol) inCH₂Cl₂ (4.0 mL) was added triethylamine (0.006 mL, 0.046 mmol) in an icebath, followed by propionyl chloride (3.41 mg, 0.037 mmol). Theresulting mixture was stirred at rt for 2 h. After concentration, theresidue was purified by preparative HPLC to afford Example 11 (morepolar fraction) (LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₄H₄₄ClN₃O₅S: 642.3;found: 642.2) and Example 12 (less polar fraction) (LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₄H₄₄ClN₃O₅S: 642.3; found: 642.3).

Examples 13 and 14

Preparation of Example 13 and Example 14

To a stirred solution of intermediate 5-1 (Example 5 and 6 Method 2,10.9 mg, 0.019 mmol) in CH₂Cl₂ (4.0 mL) was added triethyl amine (0.004mL, 0.028 mmol) in an ice bath, followed by ethyl isocyanate (1.59 mg,0.022 mmol). The resulting mixture was stirred at rt for 2 h. Afterconcentration, the residue was purified by preparative HPLC followed byprep-TLC (5% MeOH/CH₂Cl₂) to afford Example 13 (more polar fraction)(LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₄H₄₃ClN₄O₅S: 655.3; found: 655.2),and Example 14 (less polar fraction) (¹H NMR (400 MHz, chloroform-d) δ7.71 (w, 1H), 7.31 (w, 1H), 7.16 (w, 2H), 7.02 (w, 1H), 6.78 (w, 1H),5.76 (w, 2H), 4.02-3.94 (m, 2H), 3.72-2.65 (m, 11H), 2.34-0.84 (m, 17H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₄H₄₃ClN₄O₅S: 655.3; found: 655.2.

Example 15

To a stirred solution of 3-(dimethylamino)propionic acid hydrochloride(3.94 mg, 0.026 mmol) in CH₂Cl₂ (3 mL) was added Et₃N (0.01 mL, 0.068mmol), EDCI (5.32 mg, 0.034 mmol), and DMAP (4.18 mg, 0.034 mmol),followed by intermediate 5-1 (Example 5/6 Method 2, 10.00 mg, 0.017mmol). The resulting mixture was stirred at rt for 3 h and concentrated.The residue was purified by preparative HPLC to afford Example 15.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₆H₄₇ClN₄O₅S: 683.3; found: 683.3.

Examples 16 and 17

Step 1: Preparation of Intermediate 16-1

To a stirred solution of intermediate 5-1 (Example 5/6 Method 2, 20.00mg, 0.034 mmol) in MeOH (5 mL) was added Pd/C (10% weight, 0.36 mg, 0.03mmol). The resulting mixture was stirred at rt under H₂ for 1.5 h.Filtered the reaction mixture through celite, and washed with MeOH. Thefiltrate was concentrated. Crude product was used directly for nextstep.

Step 2: Preparation of Example 16 and Example 17

Crude intermediate 16-1 from step 1 was then coupled with propionylchloride and purified in similar manner to Example 11 and Example 12 togive Example 16 (less polar fraction) (LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₄H₄₅N₃O₅S: 607.8; found: 608.3) and Example 17 (more polar fraction)(LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₄H₄₅N₃O₅S: 607.8; found: 608.4.

Example 18

To a stirred solution of 3-methoxypropionic acid (2.3 mg, 0.022 mmol) inCH₂Cl₂ (2 mL) was added EDCI (4.52 mg, 0.029 mmol), and DMAP (3.56 mg,0.029 mmol), followed by Example 5 (8.50 mg, 0.015 mmol). The resultingmixture was stirred at rt for 3 h and concentrated. The residue waspurified by preparative HPLC to afford Example 18. ¹H NMR (400 MHz,Chloroform-d) δ 7.73 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.4, 2.0 Hz, 1H),7.29-7.28 (m, 1H), 7.13 (dd, J=8.4, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H),6.94 (d, J=8.4 Hz, 1H), 5.88 (dt, J=15.8, 5.0 Hz, 1H), 5.75 (dd, J=15.8,7.8 Hz, 1H), 4.05 (dd, J=32.4, 12.0 Hz, 2H), 3.95-3.73 (m, 6H), 3.60(dd, J=8.0, 3.2 Hz, 1H), 3.46 (s, 3H), 3.37 (d, J=14.4 Hz, 1H), 3.32 (s,3H), 3.04 (dd, J=15.0, 11.0 Hz, 1H), 2.80-2.71 (m, 5H), 2.43-2.28 (m,4H), 2.11-1.69 (m, 8H), 1.42-1.36 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₃₅H₄₄ClN₃O₆S: 670.3; found: 670.4.

Example 19

To a stirred solution of Example 5 (8.5 mg, 0.015 mmol) in CH₂Cl₂ (2.0mL) was added triethylamine (0.003 mL, 0.022 mmol) in an ice bath,followed by isopropyl isocyanate (1.86 mg, 0.022 mmol). The resultingmixture was stirred at rt for 2 h. After concentration, the residue waspurified by preparative HPLC followed by prep-TLC (5% MeOH/CH₂Cl₂) toafford Example 19. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₅H₄₅ClN₄O₅S:669.3; found: 691.3.

Example 20

Example 20 was synthesized in the same manner as Example 18 using2-(pyrazin-2-yl)acetic acid instead of 3-methoxypropionic acid.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₂ClN₅O₅S: 704.3; found: 704.4.

Example 21

To a stirred solution of Example 5 (10.0 mg, 0.017 mmol) in CH₂Cl₂ (2.0mL) was added triethylamine (0.004 mL, 0.026 mmol) in an ice bath,followed by cyclopropylacetyl chloride (3.04 mg, 0.026 mmol). Theresulting mixture was stirred at rt for 2 h. After concentration, theresidue was purified by preparative HPLC to afford Example 21. LCMS-ESI+(m/z): [M+H]+ calcd for C₃₆H₄₄ClN₃O₅S: 666.3; found: 666.3.

Example 22

Example 22 was synthesized in the same manner as Example 18 using3-(1-methyl-1H-pyrazol-5-yl)propanoic acid instead of 3-methoxypropionicacid. ¹H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J=2.0 Hz, 1H), 7.47 (d,J=8.8 Hz, 1H), 7.29-7.27 (m, 1H), 7.04 (d, J=2.0 Hz, 2H), 6.99 (d, J=8.0Hz, 1H), 6.64-6.61 (m, 1H), 6.33 (d, J=2.4 Hz, 1H), 5.82 (d, J=4.8 Hz,2H), 3.99-3.94 (m, 6H), 3.70-3.56 (m, 4H), 3.45-3.28 (m, 4H), 3.11-2.98(m, 4H), 2.87-2.72 (m, 4H), 2.58-1.75 (m, 12H), 1.32-1.26 (m, 1H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₆ClN₅O₅S: 720.3; found: 720.4.

Example 23

Example 23 was synthesized in the same manner as Example 21 using3,3,3-trifluoropropionyl chloride instead of cyclopropylacetyl chloride.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₄H₃₉ClF₃N₃O₅S: 694.2; found: 694.4.

Example 24

Example 24 was synthesized in the same manner as Example 18 usingoxetane-3-carboxylic acid instead of 3-methoxypropionic acid. ¹H NMR(400 MHz, Methanol-d4) δ 7.75 (d, J=8.4 Hz, 1H), 7.23 (dd, J=8.0, 2.0Hz, 1H), 7.17-7.14 (m, 2H), 7.07 (d, J=2.4 Hz, 1H), 6.79 (d, J=8.0 Hz,1H), 6.06 (dt, J=15.4, 6.2 Hz, 1H), 5.60 (dd, J=15.6, 8.8 Hz, 1H),4.90-4.76 (m, 4H), 4.17-3.93 (m, 4H), 3.91-3.79 (m, 3H), 3.72-3.47 (m,5H), 3.24 (s, 3H), 3.02 (dd, J=15.0, 10.6 Hz, 1H), 2.83-2.69 (m, 2H),2.65-1.37 (m, 11H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₅H₄₂ClN₃O₆S:668.3; found: 668.6.

Example 25

Example 25 was synthesized in the same manner Example 21 using acetylchloride instead of cyclopropylacetyl chloride. LCMS-ESI+ (m/z): [M+H]+calcd for C₃₃H₄₀ClN₃O₅S: 626.2; found: 626.4.

Example 26

Example 26 was synthesized in the same manner as Example 21 usingisovaleryl chloride instead of cyclopropylacetyl chloride. LCMS-ESI+(m/z): [M+H]+ calcd for C₃₆H₄₆ClN₃O₅S: 668.3; found: 668.4.

Example 27

Example 27 was synthesized in the same manner as Example 21 usingcyclopropylacetyl chloride instead of cyclopropylacetyl chloride.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₅H₄₂ClN₃O₅S: 652.3; found: 652.4.

Example 28

Example 28 was synthesized in the same manner as Example 18 using3-(methylsulfonyl)propanoic acid instead of 3-methoxypropionic acid.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₅H₄₄ClN₃O₇S₂: 718.3; found: 718.3.

Example 29

Example 29 was synthesized in the same manner as Example 18 using2-(1-methyl-1H-pyrazol-5-yl)acetic acid instead of 3-methoxypropionicacid. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₄ClN₅O₅S: 706.3; found:706.4.

Example 30

Example 30 was synthesized in the same manner as Example 18 using2-(pyrimidin-2-yl)acetic acid instead of 3-methoxypropionic acid.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₂ClN₅O₅S: 704.3; found: 704.3.

Example 31

Example 31 was synthesized in the same manner as Example 21 usingcyclobutanecarboxylic acid chloride instead of cyclopropylacetylchloride. ¹H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J=8.4 Hz, 1H), 7.26(d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.82(d, J=8.4 Hz, 1H), 6.10 (dt, J=15.6, 6.4 Hz, 1H), 5.60 (dd, J=15.6, 8.8Hz, 1H), 4.25-4.13 (m, 1H), 4.03 (dd, J=21.6, 12.0 Hz, 3H), 3.94-3.85(m, 2H), 3.74-3.66 (m, 2H), 3.35-3.30 (m, 2H), 3.27 (s, 3H), 3.22 0 3.14(m, 1H), 3.04 (dd, J=15.2, 10.4 Hz, 1H), 2.86-2.72 (m, 2H), 2.39-1.72(m, 17H), 1.46-1.40 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₆H₄₄ClN₃O₅S: 666.3; found: 666.4.

Example 32

Example 32 was synthesized in the same manner as Example 19 using1-isocyanato-1-(trifluoromethyl)cyclopropane instead of isopropylisocyanate. ¹H NMR (400 MHz, Methanol-d4) δ 7.75 (d, J=8.4 Hz, 1H), 7.21(d, J=8.4 Hz, 1H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 7.12 (s, 1H), 7.07 (d,J=2.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.08-6.02 (m, 1H), 5.62-5.56 (m,1H), 3.99 (dd, J=21.8, 12.2 Hz, 3H), 3.83-3.76 (m, 2H), 3.67-3.64 (m,3H), 3.34-3.30 (m, 2H), 3.24 (s, 3H), 3.07-3.00 (m, 1H), 2.83-2.69 (m,2H), 2.53-1.68 (m, 11H), 1.44-1.37 (m, 1H), 1.22-1.04 (m, 4H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₆H₄₂ClF₃N₄O₅S: 735.3; found: 735.3.

Example 33

Example 33 was synthesized in the same manner as Example 18 using2-butynoic acid instead of 3-methoxypropionic acid. LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₅H₄₀ClN₃O₅S: 650.2; found: 650.3.

Example 34

Example 34 was synthesized in the same manner as Example 19 using1,1,1-trifluoro-2-isocyanato-2-methylpropane instead of isopropylisocyanate. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₆H₄₄ClF₃N₄O₅S: 737.3;found: 737.3.

Example 35

Example 35 was synthesized in the same manner as Example 18 using3-(pyrazin-2-yl)propanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Methanol-d4) δ 8.58 (s, 1H), 8.53 (s, 1H), 8.43 (d, J=2.8Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.42-7.35 (m, 2H), 7.24-7.18 (m, 1H),7.12 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 5.92-5.80 (m, 2H), 4.11-3.94 (m,3H), 3.83-3.68 (m, 3H), 3.60-3.41 (m, 3H), 3.27 (s, 3H), 3.21-3.10 (m,3H), 2.94 (t, J=7.0 Hz, 2H), 2.85-2.78 (m, 4H), 2.48-1.80 (m, 10H), 1.45(t, J=12.8 Hz, 1H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₈H₄₄ClN₅O₅S:718.3; found: 718.3.

Example 36

Example 36 was synthesized in the same manner as Example 18 using4,4-dimethylpent-2-ynoic acid instead of 3-methoxypropionic acid.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₆ClN₃O₅S: 692.3; found: 692.3.

Example 37

Example 37 was synthesized in the same manner as Example 19 using4-fluorobenzyl isocyanate instead of isopropyl isocyanate. ¹H NMR (400MHz, Methanol-d4) δ 7.76 (d, J=8.8 Hz, 1H), 7.36-7.27 (m, 4H), 7.17 (d,J=8.4 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.04 (t, J=8.6 Hz, 2H), 6.90 (d,J=8.0 Hz, 1H), 5.99-5.93 (m, 1H), 5.77-5.71 (m, 1H), 4.36 (s, 2H), 4.05(dd, J=26.4, 12.0 Hz, 2H), 3.92 (w, 2H), 3.83 (d, J=15.2 Hz, 1H), 3.72(d, J=14.0 Hz, 1H), 3.63 (d, J=8.8 Hz, 1H), 3.51-3.38 (m, 3H), 3.30 (s,3H), 3.15-3.08 (m, 1H), 2.85-2.77 (m, 3H), 2.66-1.79 (m, 10H), 1.44 (t,J=12.8 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₄ClFN₄O₅S: 735.3;found: 735.3.

Example 38

Example 38 was synthesized in the same manner as Example 18 using3-pyrimidin-4-yl-propanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Methanol-d4) δ 9.04 (s, 1H), 8.62 (d, J=5.2 Hz, 1H), 7.78(d, J=8.4 Hz, 1H), 7.47 (d, J=5.2 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J=8.4Hz, 1H), 7.19 (dd, J=9.0, 2.2 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.91 (d,J=8.4 Hz, 1H), 5.92-5.80 (m, 2H), 4.11-3.94 (m, 3H), 3.81 (d, J=14.8 Hz,1H), 3.75 (d, J=14.4 Hz, 1H), 3.62-3.42 (m, 5H), 3.27 (s, 3H), 3.19-3.10(m, 3H), 2.94 (t, J=7.0 Hz, 2H), 2.85-2.77 (m, 3H), 2.54-1.78 (m, 10H),1.45 (t, J=12.4 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₈H₄₄ClN₅O₅S: 718.3; found: 718.3.

Example 39

Example 39 was synthesized in the same manner as Example 18 using3-pyrazol-1-yl-propionic acid instead of 3-methoxypropionic acid. ¹H NMR(400 MHz, Methanol-d4) δ 7.77 (d, J=8.4 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H),7.49 (d, J=1.6 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.34 (dd, J=8.2, 1.8 Hz,1H), 7.19 (d, J=8.0 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.4 Hz,1H), 6.26-6.25 (m, 1H), 5.94-5.79 (m, 2H), 4.49 (t, J=6.6 Hz, 2H), 4.05(dd, J=33.4, 12.2 Hz, 2H), 3.96-3.91 (m, 1H), 3.81 (d, J=15.2 Hz, 1H),3.75 (d, J=14.4 Hz, 1H), 3.68-3.55 (m, 3H), 3.51-3.41 (m, 2H), 3.31 (s,3H), 3.16-3.10 (m, 1H), 2.96 (t, J=6.6 Hz, 2H), 2.85-2.77 (m, 3H),2.46-1.79 (m, 10H), 1.45 (t, J=12.6 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₇H₄₄ClN₅O₅S: 706.3; found: 706.3.

Example 40

Example 40 was synthesized in the same manner as Example 18 using3-pyridinepropionic acid instead of 3-methoxypropionic acid. ¹H NMR (400MHz, Methanol-D4) δ 8.78 (s, 1H), 8.65 (d, J=5.6 Hz, 1H), 8.50 (d, J=8.4Hz, 1H), 7.90 (dd, J=8.0, 6.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.40 (d,J=2.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.6, 2.2 Hz, 1H),7.12 (d, J=2.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 5.92-5.81 (m, 2H),4.11-3.95 (m, 4H), 3.81-3.73 (m, 2H), 3.56-3.43 (m, 4H), 3.32 (s, 3H),3.25-3.11 (m, 3H), 2.90 (t, J=6.8 Hz, 2H), 2.85-2.78 (m, 2H), 2.26-1.80(m, 11H), 1.44 (t, J=12.8 Hz, 1H). LCMS-ESI+(m/z): [M+H]+ calcd forC₃₉H₄₅ClN₄O₅S: 717.3; found: 717.4.

Example 41

Example 41 was synthesized in the same manner as Example 18 using3-(pyridin-4-yl)propanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Methanol-d4) δ 8.64 (d, J=6.0 Hz, 2H), 7.93 (d, J=5.6 Hz,2H), 7.76 (d, J=8.4 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.31 (dd, J=8.2,1.8 Hz, 1H), 7.17 (dd, J=8.4, 2.4 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.92(d, J=8.0 Hz, 1H), 5.92-5.81 (m, 2H), 4.11-3.97 (m, 3H), 3.81-3.73 (m,2H), 3.55-3.43 (m, 3H), 3.32 (s, 3H), 3.31-3.20 (m, 3H), 3.17-3.11 (m,1H), 2.94 (t, J=7.0 Hz, 2H), 2.87-2.77 (m, 3H), 2.54-1.80 (m, 10H),1.47-1.41 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₅ClN₄O₅S:717.3; found: 717.3.

Example 42

Example 42 was synthesized in the same manner as Example 18 using3-(1H-1,2,4-triazol-1-yl)propanoic acid instead of 3-methoxypropionicacid. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₆H₄₃ClN₆O₅S: 707.3; found:707.3.

Example 43

Example 43 was synthesized in the same manner as Example 18 using3-(1-methyl-1H-imidazol-2-yl)propanoic acid instead of3-methoxypropionic acid. LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₈H₄₆ClN₅O₅S: 720.3; found: 721.3.

Example 44

Example 44 was synthesized in the same manner as Example 18 using3-(pyrimidin-2-yl)propanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Methanol-d4) δ 8.73 (d, J=4.8 Hz, 2H), 7.76 (d, J=8.8 Hz,1H), 7.40 (d, J=2.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.17 (dd, J=8.8, 2.4 Hz,1H), 7.11 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 5.93-5.79 (m, 2H),4.10-3.93 (m, 3H), 3.80 (d, J=15.2 Hz, 1H), 3.74 (d, J=14.4 Hz, 1H),3.67-3.59 (m, 1H), 3.55 (dd, J=8.2, 3.0 Hz, 1H), 3.43 (d, J=14.4 Hz,1H), 3.35-3.30 (m, 4H), 3.25 (s, 3H), 3.16-3.09 (m, 1H), 3.00 (t, J=6.8Hz, 2H), 2.86-2.73 (m, 3H), 2.52-1.78 (m, 10H), 1.47-1.41 (m, 1H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₄ClN₅O₅S: 718.3; found: 719.4.

Example 45

Example 45 was synthesized in the same manner as Example 18 using3-(1-ethyl-1H-pyrazol-5-yl)propanoic acid instead of 3-methoxypropionicacid. ¹H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J=8.4 Hz, 1H), 7.42-7.35(m, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J=8.4 Hz, 1H),6.14 (s, 1H), 5.93-5.81 (m, 2H), 4.17 (q, J=7.2 Hz, 2H), 4.11-3.94 (m,3H), 3.81 (d, J=14.8 Hz, 1H), 3.74 (d, J=14.8 Hz, 1H), 3.63-3.50 (m,2H), 3.44 (d, J=14.4 Hz, 1H), 3.34-3.31 (m, 2H), 3.31 (s, 3H), 3.17-3.10(m, 1H), 3.02-3.00 (m, 2H), 2.87-2.79 (m, 5H), 2.55-1.79 (m, 10H),1.48-1.35 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₈ClN₅O₅S:734.4; found: 734.4.

Example 46

Example 46 was synthesized in the same manner as Example 18 using3-(2-methyl-2H-1,2,3-triazol-4-yl)propanoic acid instead of3-methoxypropionic acid. ¹H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J=8.4Hz, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.19 (d,J=8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 5.96-5.90 (m, 1H),5.82 (dd, J=16.2, 8.6 Hz, 1H), 4.10-3.94 (m, 6H), 3.82 (d, J=15.2 Hz,1H), 3.74 (d, J=14.4 Hz, 1H), 3.68-3.50 (m, 2H), 3.42 (d, J=14.4 Hz,1H), 3.34-3.32 (m, 2H), 3.31 (s, 3H), 3.16-3.09 (m, 1H), 3.01 (t, J=7.2Hz, 2H), 2.85-2.75 (m, 5H), 2.50-1.78 (m, 10H), 1.48-1.42 (m, 1H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₅ClN₆O₅S: 721.3; found: 721.3.

Example 47

Example 47 was synthesized in the same manner as Example 18 using2-pyridinpropanoic acid instead of 3-methoxypropionic acid. ¹H NMR (400MHz, Methanol-d4) δ 8.60 (d, J=5.6 Hz, 1H), 8.26 (t, J=7.8 Hz, 1H), 7.82(d, J=8.0 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.69 (t, J=6.6 Hz, 1H), 7.40(s, 1H), 7.31 (dd, J=8.2, 1.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.12 (s,1H), 6.91 (d, J=8.0 Hz, 1H), 5.92-5.79 (m, 2H), 4.12-3.92 (m, 3H),3.82-3.74 (m, 2H), 3.57-3.51 (m, 2H), 3.44 (d, J=14.8 Hz, 1H), 3.29 (s,3H), 3.33-3.24 (m, 4H), 3.17-3.11 (m, 1H), 2.96 (t, J=6.8 Hz, 2H),2.92-2.78 (m, 3H), 2.49-1.81 (m, 10H), 1.48-1.41 (m, 1H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₉H₄₅ClN₄O₅S: 717.3; found: 717.5.

Example 48

Example 48 was synthesized in a same manner as Example 18 using3-(1-methyl-1H-pyrazol-5-yl)propanoic acid and Example 6 instead of3-methoxypropionic acid and Example 5. LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₈H₄₆ClN₅O₅S: 720.3; found: 720.0.

Example 49

Step 1

To a stirred solution of(3S)—N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxamide1-6 (309.00 mg, 0.483 mmol) in CH₂Cl₂ (15.0 mL) was added triethylamine(0.14 mL, 0.965 mmol) in an ice bath, followed by DMAP (23.58 mg, 0.193mmol) and di-tert-butyl dicarbonate (157.99 mg, 0.724 mmol). Theresulting mixture was stirred at rt overnight. After concentration, themixtures of diastereomers were separated by preparative HPLC to afford49-1 (less polar fraction) and 49-2 (more polar fraction).

Step 2

Intermediate 49-3 was synthesized from Intermediate 49-1 using a similarprocedure shown in Example 5, Method 1 step 2.

Step 3

Example 49 was synthesized in the same manner as Example 18 using3-(1-methyl-1H-pyrazol-5-yl)propanoic acid and intermediate 49-3. ¹H NMR(400 MHz, Methanol-d4) δ 7.75 (d, J=8.8 Hz, 1H), 7.38 (s, 1H), 7.19 (d,J=8.4 Hz, 2H), 7.13 (d, J=2.0 Hz, 1H), 7.05 (s, 1H), 6.93 (d, J=8.4 Hz,1H), 6.15 (s, 1H), 6.00-5.93 (m, 1H), 5.60 (dd, J=15.4, 9.0 Hz, 1H),4.32-4.28 (m, 1H), 4.09 (s, 2H), 3.85-3.81 (m, 4H), 3.75-3.67 (m, 3H),3.51-3.79 (m, 1H), 3.25 (s, 3H), 3.16-3.09 (m, 1H), 3.01 (t, J=12 Hz,2H), 2.85-2.79 (m, 5H), 2.48-1.77 (m, 10H), 1.51-1.44 (m, 4H), 1.06 (d,J=5.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₅₀ClN₅O₅S: 748.4;found: 748.0.

Example 50

Example 50 was synthesized with the procedure described in Example 49(step 2 and Step 3) using intermediate 49-2 instead of intermediate49-1. LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₅₀ClN₅O₅S: 748.4; found:748.0.

Example 51

Example 51 was synthesized in the same manner as Example 18 using3-(1-methyl-1H-pyrazol-3-yl)propanoic acid instead of 3-methoxypropionicacid. ¹H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J=8.4 Hz, 1H), 7.44 (d,J=8.4 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.12 (s,1H), 6.90 (d, J=8.4 Hz, 1H), 6.12 (d, J=2.4 Hz, 1H), 5.94-5.81 (m, 2H),4.11-3.94 (m, 3H), 3.83-3.80 (m, 4H), 3.75 (d, J=14.4 Hz, 1H), 3.68-3.47(m, 2H), 3.43 (d, J=14.8 Hz, 1H), 3.34-3.31 (m, 5H), 3.16-3.10 (m, 1H),2.94 (t, J=7.8 Hz, 2H), 2.85-2.78 (m, 3H), 2.74 (t, J=7.6 Hz, 2H),2.53-1.78 (m, 10H), 1.45 (t, J=12.6 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₈H₄₆ClN₅O₅S: 720.3; found: 720.0.

Example 52

Example 52 was synthesized in the same manner as Example 18 using3-indazol-1-yl-propanoic acid instead of 3-methoxypropionic acid.LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₁H₄₆ClN₅O₅S: 756.4; found: 756.2.

Example 53

Example 53 was synthesized in the same manner as Example 18 using3-(pyrimidin-5-yl)propanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Methanol-d4) δ 9.00 (s, 1H), 8.74 (s, 2H), 7.77 (d, J=8.4Hz, 1H), 7.41 (s, 1H), 7.34 (dd, J=8.0, 1.6 Hz, 1H), 7.17 (d, J=8.4 Hz,1H), 7.11 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.92-5.81 (m, 2H), 4.11-3.91(m, 3H), 3.82-3.68 (m, 2H), 3.60-3.50 (m, 2H), 3.43 (d, J=14.4 Hz, 1H),3.35-3.33 (m, 5H), 3.16-3.10 (m, 1H), 3.02 (t, J=7.3 Hz, 2H), 2.87-2.78(m, 4H), 2.55-1.78 (m, 10H), 1.44 (t, J=12.8 Hz, 1H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₈H₄₄ClN₅O₅S: 718.3; found: 718.1.

Example 54

Example 54 was synthesized in the same manner as Example 18 using sodium3-(1H-1,2,3-triazol-1-yl)propanoic acid instead of 3-methoxypropionicacid. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₆H₄₃ClN₆O₅S: 707.3; found:707.1.

Example 55

Example 55 was synthesized in the same manner as Example 18 using3-(4-chloro-1H-pyrazol-1-yl)propanoic acid instead of 3-methoxypropionicacid. ¹H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J=8.8 Hz, 1H), 7.73 (s,1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.94-5.79 (m,2H), 4.44 (t, J=6.2 Hz, 2H), 4.05 (dd, J=33.8, 12.2 Hz, 2H), 3.97-3.89(m, 1H), 3.81 (d, J=14.8 Hz, 1H), 3.75 (d, J=14.4 Hz, 1H), 3.64-3.50 (m,2H), 3.43 (d, J=14.4 Hz, 1H), 3.34-3.31 (m, 5H), 3.16-3.10 (m, 1H), 2.96(t, J=6.4 Hz, 2H), 2.85-2.77 (m, 3H), 2.53-1.79 (m, 10H), 1.45 (t,J=12.6 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₃Cl₂N₅O₅S: 740.7;found: 740.0.

Example 56

Example 56 was synthesized in the same manner as Example 18 using3-(5-methyl-1H-pyrazol-1-yl)propanoic acid. LCMS-ESI+ (m/z): [M+H]+calcd for C₃₈H₄₆ClN₅O₅S: 720.3; found: 720.1.

Example 57

Example 57 was synthesized in the same manner as Example 18 using3-isoxazol-4-yl-propanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.35 (s, 1H), 7.77 (d, J=8.8Hz, 1H), 7.42 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H),7.12 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 5.93-5.81 (m, 2H), 4.11-3.92 (m,3H), 3.81 (d, J=15.2 Hz, 1H), 3.75 (d, J=14.4 Hz, 1H), 3.64-3.49 (m,2H), 3.44 (d, J=14.4 Hz, 1H), 3.36-3.31 (m, 7H), 3.17-3.10 (m, 1H),2.87-2.77 (m, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.55-1.79 (m, 10H), 1.45 (t,J=12.6 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₃ClN₄O₆S: 707.3;found: 707.1.

Example 58

Example 58 was synthesized in the same manner as Example 18 using3-(1,2-oxazol-3-yl)propanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Methanol-74) δ 8.54 (d, J=1.6 Hz, 1H), 7.77 (d, J=8.8 Hz,1H), 7.40 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.12(d, J=2.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.43 (d, J=1.6 Hz, 1H),5.95-5.89 (m, 1H), 5.82 (dd, J=16.0, 8.4 Hz, 1H), 4.11-3.92 (m, 3H),3.82 (d, J=15.2 Hz, 1H), 3.74 (d, J=14.4 Hz, 1H), 3.68-3.47 (m, 2H),3.42 (d, J=14.4 Hz, 1H), 3.35-3.32 (m, 2H), 3.31 (s, 3H), 3.16-3.04 (m,3H), 2.85-2.72 (m, 5H), 2.51-1.78 (m, 10H), 1.45 (t, J=12.6 Hz, 1H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₃ClN₄O₆S: 707.3; found: 707.0.

Example 59

Example 59 was synthesized in the same manner as Example 18 using3-(3-methyl-1H-pyrazol-1-yl)propanoic acid instead of 3-m ethoxypropionic acid. H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J=8.8 Hz, 1H),7.51 (d, J=2.4 Hz, 1H), 7.41 (s, 1H), 7.34 (dd, J=8.2, 1.8 Hz, 1H), 7.19(d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.02 (d, J=2.4Hz, 1H), 5.95-5.80 (m, 2H), 4.39 (t, J=6.6 Hz, 2H), 4.06 (dd, J=34.2,12.2 Hz, 2H), 3.98-3.91 (m, 1H), 3.81 (d, J=15.2 Hz, 1H), 3.75 (d,J=14.4 Hz, 1H), 3.68-3.47 (m, 2H), 3.43 (d, J=14.4 Hz, 1H), 3.35-3.31(m, 5H), 3.16-3.10 (m, 1H), 2.93 (t, J=6.4 Hz, 2H), 2.85-2.75 (m, 3H),2.53-1.79 (m, 13H), 1.45 (t, J=12.6 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₈H₄₆ClN₅O₅S: 720.3; found: 720.1.

Example 60

Example 60 was synthesized in the same manner as Example 18 usinglithium 3-(5-methyl-1,3,4-oxadiazol-2-yl)propanoate instead of3-methoxypropionic acid. LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₇H₄₄ClN₅O₆S: 722.3; found: 722.1.

Example 61

Example 61 was synthesized in the same manner as Example 18 using3-(4-methyl-1H-pyrazol-1-yl)propanoic acid instead of 3-methoxypropionicacid. ¹H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J=8.4 Hz, 1H), 7.41 (s,2H), 7.34 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.12(s, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.93-5.80 (m, 2H), 4.40 (td, J=6.4, 2.4Hz, 2H), 3.81 (dd, J=34.0, 12.4 Hz, 2H), 3.97-3.90 (m, 1H), 3.81 (d,J=14.8 Hz, 1H), 3.75 (d, J=14.4 Hz, 1H), 3.63-3.47 (m, 2H), 3.43 (d,J=14.8 Hz, 1H), 3.35-3.33 (m, 5H), 3.17-3.10 (m, 1H), 2.92 (t, J=6.6 Hz,2H), 2.85-2.75 (m, 3H), 2.52-1.78 (m, 13H), 1.45 (t, J=12.8 Hz, 1H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₆ClN₅O₅S: 720.3; found: 720.1.

Examples 62 and 63

Step 1

To a stirred solution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (2.0 g, 4.27 mmol) intetrahydrofuran was added pyridine (1.0 g, 8.5 mmol) and aceticanhydride (1.3 g, 8.5 mmol). Mixture was stirred at room temperature for48 hours followed by evaporation of the solvents. The residue wasdissolved in ethyl acetate and washed with water. The organic layer wasconcentrated to give the crude anhydride 62-1.

Step 2

A stirred solution of anhydride 62-1 (2.0 gr, 3.6 mmol) in CH₂Cl₂ wascooled down to 0° C. To this mixture SOCl₂ (2 mL) was added dropwiseunder vigorous stirring. The mixture was stirred at 0° C. and let itwarm slowly to room temperature. After reaction was completed it wasevaporated to remove excess SOCl₂ to give acid chloride intermediate62-2 that was used on next step immediately.

Step 3

To a solution of 62-2 (200 mg, 0.38 mmol) and pyridazine (30 mg, 0.38mmol) in acetonitrile stirred for 5 min at room temperature was addedthe racemic mixture of(S)—N′-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide and(R)—N′-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide (99 mg,0.38 mmol). After completion of the reaction, the residue was dissolvedin ethyl acetate and washed with water. The organic layer wasconcentrated and purified by reversed phase chromatographyAcetonitrile-water 50%-90% for 30 min to give diastereomeric mixture ofIntermediate IV.

Step 4

A mixture of sulfonimidamide intermediate IV (150 mg, 0.23 mmol),propionyl chloride (26 mg, 0.29 mmol), and triethylamine (0.29 mmol) wasstirred at room temperature in CH₂Cl₂ for one hour. The reaction mixturewas evaporated under reduced pressure, dissolved in DMF and purified byreversed phase chromatography, acetonitrile-water 50-90% for 30 min toyield 62-3.

Step 5

Ester intermediate 62-3 (25 mg, 0.036 mmol) and Hoveyda-Grubbs 2^(nd)generation catalyst (2.2 mg, 0.004 mmol) was sealed in a microwave vialand purged with argon and then 1,2-DCE was added. The microwave vial washeated to 60° C. for 1 hour. After completion of the reaction, thereaction mixture was evaporated under reduced pressure, dissolved in DMFand purified by reversed phase chromatography acetonitrile-water 50%-90%for 30 min to yield the macrocycle intermediate 62-4 as mixture ofdiastereomers.

Step 6

Intermediate (62-4) were dissolved in methanol (3 mL) and water (0.3mL). To this solution K₂CO₃ (10.8 mg, 0.08 mmol) was added and stirredat room temperature for 7 hr. The mixture was dissolved in ethyl acetateand washed with water. The organic layer was concentrated and purifiedby reversed phase chromatography Acetonitrile-water 50%-90% for 30 minto give Example 62 (less polar fraction) and Example 63 (more polarfraction).

Example 62

¹H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J=8.5 Hz, 1H), 7.38 (d, J=8.9Hz, 2H), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.92 (d,J=8.0 Hz, 1H), 6.00 (dd, J=15.8, 7.6 Hz, 1H), 5.80 (dt, J=15.8, 5.2 Hz,1H), 4.20-3.95 (m, 4H), 3.78 (t, J=14.7 Hz, 3H), 3.53-3.40 (m, 3H), 3.34(d, J=14.4 Hz, 2H), 3.15-3.00 (m, 2H), 2.88-2.67 (m, 3H), 2.45 (q, J=7.5Hz, 3H), 2.24 (dt, J=12.7, 6.3 Hz, 2H), 2.12-1.63 (m, 4H), 1.40 (d,J=13.3 Hz, 1H), 1.26 (t, J=7.1 Hz, 1H), 1.17 (t, J=7.4 Hz, 2H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₃H₄₀ClN₃O₅S: 626.2; found: 626.2.

Example 63

¹H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.72 (d, J=8.5 Hz, 1H),7.44-7.33 (m, 2H), 7.18 (d, J=8.2 Hz, 1H), 7.08 (s, 1H), 6.91 (t, J=8.1Hz, 1H), 5.91-5.71 (m, 2H), 4.15-4.00 (m, 3H), 3.99-3.85 (m, 1H), 3.71(d, J=14.7 Hz, 2H), 3.58 (d, J=14.9 Hz, 1H), 3.43 (d, J=14.7 Hz, 1H),3.27 (s, 2H), 3.00 (s, 2H), 2.95-2.87 (m, 2H), 2.80 (d, J=19.0 Hz, 3H),2.46 (tt, J=7.4, 3.4 Hz, 3H), 1.90-1.60 (m, 6H), 1.23 (dt, J=18.1, 7.3Hz, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₃H₄₀ClN₃O₅S: 626.2; found:626.2.

Examples 64 and 65

Step 1: Preparation of(R)—N-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonamide

To a stirred solution of (R)-hept-6-ene-3-sulfonamide (preparedaccording to the procedure in International Publication No. WO17/147410,1.5 g, 9.2 mmol) in THF was added Et₃N (1.8 g, 18.3 mmol) in an icebath, followed by tert-butylchloro dimethylsilane (1.7 g, 11.5 mmol) inTHF. The resulting mixture was stirred at room temperature for 24 hrs.The precipitate was filtered off and washed with ether. The filtrate wasconcentrated and purified on normal phase chromatographyHexanes/EtOAc=3:1 to yield(R)—N-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonamide.

Step 2: Preparation of(3R)—N′-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimidamide

To a stirred suspension of Ph₃PCl₂ (4.2 g, 12.6 mmol) in CH₂Cl₂ under anitrogen atmosphere, was added triethylamine (1.2 g, 12.6 mmol). Themixture was stirred for 10 min at room temperature, then cooled to 0° C.and a solution of(R)—N-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonamide (2.2 g, 7.9mmol) in CH₂Cl₂ was added. The reaction mixture was stirred for 1 hourat 0° C. To the reaction mixture was bubbled in ammonia gas. The mixturewas stirred at 0° C. for 2 hours and then to room temperature for 24hours. The precipitate was filtered off, and washed with CH₂Cl₂. Thefiltrate was concentrated and purified on normal phase chromatography(Hexanes:EtOAc=7:3) to yield(3R)—N′-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimidamide. ¹H NMR(400 MHz, Chloroform-d) δ 5.78 (ddt, J=16.9, 10.5, 6.6 Hz, 1H),5.13-4.85 (m, 2H), 4.38 (s, 2H), 2.75 (tt, J=7.0, 4.8 Hz, 1H), 2.32-2.10(m, 2H), 2.06-1.86 (m, 2H), 1.79-1.54 (m, 2H), 1.03 (td, J=7.5, 1.7 Hz,3H), 0.87 (s, 9H), 0.09 (d, J=1.1 Hz, 6H).

Step 3

Example 64 and Example 65 were prepared in the same manner as Example 3and Example 4 using(3R)—N′-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimidamide instead ofN′-(tert-butyldimethylsilyl)pent-4-ene-1-sulfonimidamide.

Example 64 (More Polar Fraction)

¹H NMR (400 MHz, Chloroform-d) δ 7.70 (t, J=8.2 Hz, 1H), 7.35 (d, J=8.5Hz, 1H), 7.16 (t, J=4.2 Hz, 2H), 7.07 (s, 1H), 6.87 (d, J=8.0 Hz, 1H),5.86 (s, 1H), 5.59 (dd, J=15.8, 7.8 Hz, 1H), 4.18-3.95 (m, 3H),3.85-3.63 (m, 3H), 3.35-3.21 (m, 4H), 3.07-2.92 (m, 1H), 2.77 (s, 2H),2.44 (t, J=7.9 Hz, 7H), 2.18-1.57 (m, 10H), 1.25 (s, 1H), 1.13 (dt,J=28.4, 7.2 Hz, 6H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₆H₄₆ClN₃O₅S:668.2; found: 668.3.

Example 65 (Less Polar Fraction)

¹H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J=8.5 Hz, 1H), 7.17 (d, J=10.5Hz, 2H), 7.08 (s, 2H), 6.92 (d, J=8.2 Hz, 1H), 6.10-6.00 (m, 1H), 5.50(dd, J=15.4, 8.5 Hz, 1H), 4.29-3.99 (m, 3H), 3.87-3.59 (m, 3H), 3.25 (s,4H), 3.00 (s, 1H), 2.76 (d, J=13.4 Hz, 2H), 2.43 (dd, J=19.8, 12.5 Hz,6H), 2.24-1.54 (m, 11H), 1.41 (s, 1H), 1.28-1.05 (m, 6H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₆H₄₆ClN₃O₅S: 668.2; found: 668.3.

Example 66 Step 1: Preparation of 66-1

A mixture of intermediate IV (900 mg, 1.4 mmol), di-tert-butyldicarbonate (429 mg, 1.9 mmol), DMAP (17 mg, 0.14 mmol) andtriethylamine (0.2 mL) was stirred at room temperature in CH₂Cl₂ for onehour. After completion of the reaction, the reaction mixture wasevaporated under reduced pressure and purified by silica gelchromatography (Hex:EtOAc 1:1) to give intermediate 66-1.

Step 2

In a round bottle flask was added 66-1 (880 mg, 1.26 mmol) andHoveyda-Grubbs 2^(nd) generation catalyst (78 mg, 0.13 mmol). Flask wassealed and purged with argon and then 1,2-DCE was added. The flask washeated to 60° C. for 1 hour. After completion of the reaction, thereaction mixture was evaporated under reduced pressure to yieldintermediate 66-2.

Step 3

Intermediate 66-2 (600 mg, 0.84 mmol) were dissolved in methanol (6 mL)and water (0.6 mL). To this solution K₂CO₃ (406 mg, 2.94 mmol) was addedand stirred at room temperature for 7 hours. The mixture was dissolvedin ethyl acetate and washed with water. The organic layer wasconcentrated and purified by reversed phase chromatography(Acetonitrile-water 50%-90% for 30 min) to give diastereomers 66-3 (morepolar fraction) and 66-4 (less polar fraction).

Step 4

Intermediate 66-3 (15 mg, 0.024 mmol) was dissolved in DMF and NaH (4mg, 0.072 mmol) was added at room temperature, stirred for 10 min andthen 2-bromoethyl trifluoromethanesulfonate (12 mg, 0.048 mmol) wasadded. The reaction mixture was stirred at room temperature for 5 hoursand dissolved in ethyl acetate and washed with water. The organic layerwas concentrated to give Bromo intermediate 66-5 which was used furtherwithout purification.

Step 5

Bromo intermediate 66-5 (15 mg, 0.02 mmol) was dissolved in morpholineand stirred at 50° C. for 1 hour. This mixture was evaporated underreduced pressure to give 66-6 which was used further withoutpurification.

Step 6

Morpholine intermediate 66-6 (9 mg, 0.011 mmol) was treated with amixture of CH₂Cl₂ (2 mL) and TFA (1 mL) and stirred at room temperaturefor 1 h. Mixture was dissolved in ethyl acetate and washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasconcentrated and purified by reversed phase chromatographyacetonitrile-water 50%-90% for 30 min to intermediate 66-7.

Step 7

Intermediate 66-7 (5 mg, 0.007 mmol), propionyl chloride (1 mg, 0.007mmol), and triethylamine (0.021 mmol) was stirred at room temperature inCH₂Cl₂ for one hour. After completion of reaction it was evaporatedunder reduced pressure, dissolved in DMF and purified by reversed phasechromatography, acetonitrile-water 50-90% for 30 min to give Example 66.1H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J=8.5 Hz, 1H), 7.46-7.39 (m,1H), 7.31 (s, 1H), 7.22-7.15 (m, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.92 (d,J=8.3 Hz, 1H), 5.94 (d, J=15.8 Hz, 1H), 5.73 (dd, J=15.9, 7.8 Hz, 1H),4.10 (d, J=12.0 Hz, 1H), 4.03-3.75 (m, 7H), 3.66 (t, J=13.1 Hz, 5H),3.51 (d, J=12.0 Hz, 1H), 3.36 (d, J=14.4 Hz, 2H), 3.27 (s, 2H),3.14-2.92 (m, 3H), 2.76 (d, J=14.8 Hz, 3H), 2.53-2.39 (m, 3H), 2.32-1.64(m, 10H), 1.41 (d, J=12.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₉H₅₁ClN₄O₆S: 739.3; found: 739.5.

Example 67

Example 67 was synthesized in the same manner as Example 66 usingintermediate 66-4 (less polar fraction). 1H NMR (400 MHz, Chloroform-d)δ 7.74 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.32 (s, 1H), 7.18(dd, J=8.6, 2.3 Hz, 1H), 7.08 (s, 1H), 6.93 (d, J=8.3 Hz, 1H), 5.83 (s,2H), 4.11 (d, J=12.1 Hz, 1H), 3.99-3.75 (m, 6H), 3.61 (dd, J=37.3, 15.1Hz, 6H), 3.49 (s, 1H), 3.40 (s, 1H), 3.32-3.18 (m, 2H), 3.06-2.97 (m,1H), 2.90 (s, 2H), 2.82-2.66 (m, 3H), 2.49 (s, 4H), 2.28-1.62 (m, 9H),1.37 (s, 2H), 1.27-1.11 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₉H₅₁ClN₄O₆S: 739.3; found: 739.5.

Example 68

Example 68 was synthesized in the same manner as Example 67 usingintermediate 67-4 (less polar fraction) and 1-methylpiperazine insteadof morpholine. ¹H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J=8.5 Hz, 1H),7.47-7.30 (m, 2H), 7.21-7.13 (m, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.92 (d,J=8.3 Hz, 1H), 6.11 (dd, J=15.9, 9.0 Hz, 1H), 5.75 (d, J=15.9 Hz, 1H),4.12-3.93 (m, 4H), 3.85-3.49 (m, 8H), 3.36 (t, J=14.1 Hz, 4H), 3.16-3.00(m, 3H), 2.87 (d, J=10.7 Hz, 4H), 2.82-2.60 (m, 4H), 2.09 (td, J=15.4,14.9, 8.0 Hz, 6H), 1.98-1.59 (m, 6H), 1.46 (d, J=3.0 Hz, 1H), 1.42-1.20(m, 2H), 1.12 (t, J=7.1 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₀H₅₄ClN₅O₅S: 752.3; found: 752.4.

Example 69 Step 1

N′-(tert-butyldimethylsilyl)hex-5-ene-1-sulfonimidamide was prepared inthe same manner as Example 1 (step 4 and step 5) usinghex-5-ene-1-sulfonamide instead of(2R,3S)-3-methylhex-5-ene-2-sulfonamide. ¹H NMR (400 MHz, Chloroform-d)δ 5.87-5.63 (m, 1H), 5.07-4.84 (m, 2H), 4.71-4.01 (m, 2H), 3.04 (dddd,J=13.4, 10.0, 8.5, 5.0 Hz, 2H), 2.13-2.01 (m, 2H), 1.92-1.71 (m, 2H),1.57-1.45 (m, 2H), 0.88 (d, J=5.9 Hz, 9H), 0.11-0.2 (m, 6H).

Step 2: Preparation of Intermediate 69-2

To a mixture of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonylchloride (from Example 1 step 3, 200 mg, 0.40 mmol) and pyridazine (32mg, 0.40 mmol) in acetonitrile stirred for 5 min at room temperature wasadded N′-(tert-butyldimethylsilyl)hex-5-ene-1-sulfonimidamide 70-1, (121mg, 0.44 mmol). After completion of the reaction the residue wasdissolved in ethyl acetate and washed with water. The organic layer wasconcentrated and purified by normal phase chromatography Hex:AtOAc 1:1to yield 69-2 as mixture of diastereomers.

Step 3: Preparation of Intermediate 69-3

Diastereomeric mixture 69-2 (160 mg, 0.25 mmol), propionyl chloride (28mg, 0.30 mmol), and triethylamine (0.56 mmol) was stirred at roomtemperature in CH₂Cl₂ for one hour. After completion of the reaction,the reaction mixture was evaporated under reduced pressure, dissolved inDMF and purified by reversed phase chromatography, acetonitrile-water50-90% for 30 min to yield 69-3 as mixture of the diastereoisomers.

Step 4: Preparation of Example 69

In a microwave vial was added the intermediate 69-3 (25 mg, 0.037 mmol)and Hoveyda-Grubbs II (2.2 mg, 0.004 mmol). Vial was sealed and purgedwith argon and then 1,2-DCE was added. The microwave vial was heated to60° C. for one hour. After completion of the reaction, the reactionmixture was evaporated under reduced pressure, dissolved in DMF andpurified by reversed phase chromatography acetonitrile-water 50-90% for30 min to yield Example 69 (less polar fraction). ¹H NMR (400 MHz,Chloroform-d) δ 7.67 (dd, J=8.6, 4.6 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H),7.32-7.05 (m, 3H), 6.96 (dd, J=18.1, 8.1 Hz, 1H), 5.63-5.30 (m, 2H),4.25-4.01 (m, 2H), 3.86-3.56 (m, 4H), 3.49-3.27 (m, 5H), 3.22 (d, J=10.0Hz, 2H), 2.76 (d, J=10.8 Hz, 2H), 2.58-2.37 (m, 4H), 2.15-1.74 (m, 10H),1.63 (dt, J=18.7, 9.4 Hz, 6H), 1.23 (t, J=7.5 Hz, 2H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₅H₄₄ClN₃O₅S: 654.4; found: 654.2.

Examples 70 and 71

Examples 71 and 72 were synthesized in the same manner as Example 3 and4 using (3R)—N′-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimidamide(Example 64 and 65 step 1) and 3-(1-methyl-1H-pyrazol-5-yl)propanoicacid.

Example 70

¹H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J=8.5 Hz, 1H), 7.55 (d, J=2.2Hz, 1H), 7.16 (td, J=8.5, 2.3 Hz, 1H), 7.09-7.01 (m, 2H), 7.00-6.87 (m,2H), 6.16 (d, J=2.1 Hz, 1H), 5.94-5.80 (m, 1H), 5.51 (dd, J=15.3, 8.7Hz, 1H), 4.31 (s, 1H), 4.12-4.02 (m, 2H), 3.93 (s, 2H), 3.78 (t, J=13.6Hz, 1H), 3.71-3.59 (m, 4H), 3.25 (d, J=15.2 Hz, 3H), 3.05-2.89 (m, 6H),2.87-2.72 (m, 4H), 2.48-2.19 (m, 4H), 2.16-1.57 (m, 11H), 1.49-1.30 (m,1H), 1.16 (t, J=7.5 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₀H₅₀ClN₅O₅S: 748.2; found: 748.3.

Example 71

¹H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J=8.5 Hz, 1H), 7.52 (d, J=2.1Hz, 1H), 7.49-7.31 (m, 2H), 7.16 (dd, J=8.5, 2.4 Hz, 1H), 7.07 (d, J=2.3Hz, 1H), 6.91 (dd, J=11.6, 8.3 Hz, 2H), 6.15 (d, J=2.1 Hz, 1H), 5.72(td, J=10.8, 5.0 Hz, 1H), 5.37 (t, J=10.3 Hz, 1H), 4.10 (q, J=9.0, 8.0Hz, 3H), 3.98-3.55 (m, 5H), 3.48-3.35 (m, 1H), 3.35-3.14 (m, 4H),3.11-2.63 (m, 9H), 2.46-2.14 (m, 5H), 2.12-1.52 (m, 10H), 1.45-1.34 (m,1H), 1.14 (q, J=5.1, 2.9 Hz, 1H), 1.03-0.82 (m, 2H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₄₀H₅₀ClN₅O₅S: 748.2; found: 748.3.

Example 72

Example 72 was synthesized in the same manner as Example 18 using(S)-3-hydroxy-3-phenylpropanoic acid instead of 3-methoxypropionic acid.¹H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J=8.5 Hz, 1H), 7.44-7.27 (m,6H), 7.16 (d, J=1.7 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.92 (d, J=8.3 Hz,2H), 5.88-5.66 (m, 2H), 5.25 (dd, J=9.9, 2.7 Hz, 1H), 3.99 (q, J=12.0Hz, 3H), 3.71 (dd, J=27.2, 14.6 Hz, 3H), 3.56 (dd, J=7.5, 3.2 Hz, 1H),3.32 (s, 4H), 3.03 (dd, J=15.6, 10.2 Hz, 2H), 2.87-2.64 (m, 4H),2.47-2.06 (m, 5H), 2.06-1.66 (m, 5H), 1.29 (d, J=30.9 Hz, 4H). LCMS-ESI+(m/z): [M+H]+ calcd for C₄₀H₄₆ClN₃O₆S: 732.2; found: 732.0.

Example 73

To a solution of Example 5 (12 mg, 0.021 mmol) and diisopropylethylamine(0.041 mmol) in 3 mL dichloromethane was added dropwise a solution ofthiomorpholine-4-carbonyl chloride 1,1-dioxide (8 mg, 0.041 mmol) in 1mL dichloromethane and the mixture was allowed to stir at reflux for 16hrs. LC/MS showed completion of the reaction. The solvent was evaporatedunder reduced pressure and the residue was dissolved in 3 mL methanoland purified using HPLC to afford Example 73. ¹H NMR (400 MHz,Chloroform-d) δ 7.77-7.62 (m, 1H), 7.23-7.11 (m, 2H), 7.08 (d, J=2.3 Hz,1H), 7.04-6.81 (m, 2H), 5.93-5.74 (m, 1H), 5.53 (dd, J=15.5, 8.4 Hz,1H), 4.28-3.85 (m, 7H), 3.79-3.49 (m, 4H), 3.40-3.20 (m, 4H), 2.99 (d,J=34.6 Hz, 4H), 2.85-2.61 (m, 2H), 2.55-2.20 (m, 4H), 2.20-1.58 (m, 9H),1.42 (t, J=12.8 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₆H₄₅ClN₄O₇S₂: 745.25; found:745.96.

Example 74

Example 74 was synthesized in the same manner as Example 73 usingExample 6. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₆H₄₅ClN₄O₇S₂: 745.25;found: 745.96.

Example 75

A solution of the Example 5 (12 mg, 0.021 mmol), diphenylcarbonate (5mg, 0.023 mmol)) and DMAP (15 mg, 0.123 mmol) in 3 mL acetonitrile wasallowed to stir at rt for 16 hrs. (1-Methyl-1H-pyrazol-5-yl)methanamine(6.8 mg, 0.062 mmol) was added and the mixture was further stirred at rtfor 1 hr. LC/MS showed completion of the reaction. The solvent wasevaporated under reduced pressure and the residue was dissolved in 3 mLmethanol and purified using HPLC to afford Example 75. ¹H NMR (400 MHz,Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H), 7.49-7.20 (m, 3H), 7.20-7.03 (m,2H), 6.87 (d, J=8.2 Hz, 1H), 6.37 (d, J=1.9 Hz, 1H), 6.00-5.68 (m, 2H),5.38-5.16 (m, 2H), 4.21-3.90 (m, 2H), 3.82-3.47 (m, 3H), 3.46-3.18 (m,11H), 3.10 (dd, J=15.0, 10.7 Hz, 1H), 2.93-2.60 (m, 3H), 2.58-2.15 (m,3H), 2.15-1.64 (m, 6H), 1.52-1.17 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₃₇H₄₅ClN₆O₅S: 721.29; found:721.91.

Example 76

Example 76 was synthesized in the same manner as Example 75 usingExample 6 and N-methylethanamine. LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₅H₄₅ClN₄O₅S: 669.28; found: 669.88.

Example 77

Example 77 was synthesized in the same manner as Example 77 usingN-methylethanamine. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₅H₄₅ClN₄O₅S:669.28; found: 669.88.

Example 78

Example 78 was synthesized in the same manner as Example 76 using(1-methyl-1H-pyrazol-5-yl)methanol. LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₇H₄₄ClN₅O₆S: 722.27; found: 723.24.

Example 79

Example 79 was synthesized in the same manner as Example 76 usingpyridin-4-ylmethanamine. 1H NMR (400 MHz, Methanol-d4) δ 8.70 (d, J=6.0Hz, 2H), 7.96 (d, J=6.0 Hz, 2H), 7.68 (dd, J=8.9, 6.4 Hz, 1H), 7.41-7.16(m, 2H), 7.18-6.98 (m, 2H), 6.91 (d, J=8.2 Hz, 1H), 5.89 (dt, J=15.8,5.3 Hz, 1H), 5.76 (t, J=12.0 Hz, 1H), 4.64 (s, 2H), 4.21-3.46 (m, 6H),3.39 (d, J=14.5 Hz, 1H), 3.34 (s, 6H), 3.10 (dd, J=15.1, 10.8 Hz, 1H),2.97-2.58 (m, 3H), 2.35 (d, J=58.3 Hz, 3H), 2.19-1.68 (m, 6H), 1.54-1.17(m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₄ClN₅O₅S: 718.28;found:719.76.

Example 80

Example 80 was synthesized in the same manner as Example 76 usingpyrazin-2-ylmethanamine. ¹H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 1H),8.60-8.41 (m, 2H), 7.74 (dd, J=8.5, 5.2 Hz, 1H), 7.29 (dd, J=12.5, 8.1Hz, 2H), 7.23-7.00 (m, 2H), 6.86 (dd, J=16.3, 8.1 Hz, 1H), 5.89 (dt,J=15.8, 5.3 Hz, 1H), 5.76 (t, J=12.0 Hz, 1H), 4.64 (s, 2H), 4.21-3.46(m, 6H), 3.39 (d, J=14.5 Hz, 1H), 3.34 (s, 6H), 3.10 (dd, J=15.1, 10.8Hz, 1H), 2.97-2.58 (m, 3H), 2.35 (d, J=58.3 Hz, 3H), 2.19-1.68 (m, 6H),1.54-1.17 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₃ClN₆O₅S:719.27; found: 719.71.

Example 81

Example 81 was synthesized in the same manner as Example 18 using3-cyclopropylpropanoic acid instead of 3-methoxypropionic acid. 1H NMR(400 MHz, Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H),7.33 (dd, J=8.3, 1.9 Hz, 1H), 7.18-7.05 (m, 2H), 6.87 (d, J=8.2 Hz, 1H),5.93-5.76 (m, 2H), 4.06 (d, J=12.1 Hz, 1H), 4.02-3.89 (m, 2H), 3.78 (d,J=14.9 Hz, 1H), 3.71 (d, J=14.3 Hz, 1H), 3.67-3.46 (m, 2H), 3.40 (d,J=14.4 Hz, 1H), 3.34 (s, 1H), 3.25 (s, 3H), 3.11 (dd, J=15.3, 10.8 Hz,1H), 2.82-2.72 (m, 2H), 2.47 (t, J=7.3 Hz, 3H), 2.26-2.17 (m, 1H),2.13-1.98 (m, 3H), 1.93 (s, 1H), 1.77 (t, J=6.3 Hz, 2H), 1.53 (q, J=7.2Hz, 2H), 1.41 (t, J=13.1 Hz, 2H), 1.28 (s, 2H), 0.89 (t, J=6.6 Hz, 1H),0.80-0.68 (m, 1H), 0.48-0.39 (m, 2H), 0.08 (t, J=4.7 Hz, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₇H₄₆ClN₃O₅S: 680.29; found: 680.98.

Example 82

Example 82 was synthesized in the same manner as Example 18 using3-cyclopentylpropanoic acid instead of 3-methoxypropionic acid.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₅₀ClN₃O₅S: 709.32; found: 709.36.

Examples 83 and 84 Step 1: Preparation of trans-(±)-ethyl2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylate

Sodium hydride (0.22 g, 9.1 mmol) and trimethyl sulfoxonium iodide (1.4g, 18.1 mmol) were stirred for one hour in 7 mL DMSO at roomtemperature. Ethyl (E)-3-(1-methyl-1H-pyrazol-5-yl)acrylate (0.65 g, 3.6mmol) was dissolved in 5 mL DMSO/THF (1:1) and added to the reactionmixture. After completion of the reaction (3 h, LC/MS) 1 N HCl is addedand the reaction mixture extracted with diethyl ether. The combinedorganic layers are dried over MgSO₄, the solvent was removed and thecrude product was used without further purification.

Step 2: Preparation of trans(±)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic Acid

To a solution of trans-(±)-ethyl2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylate (0.4 g, 2.4 mmol)in 10 mL methanol was added 2 mL of 1 N NaOH and the reaction wasstirred at rt for 3 hr. Methanol was removed under reduced pressure andaqueous solution was acidified to pH 4 using concentrated HCl. Theprecipitate formed was collected by filtration, washed with water andair-dried to give the acid which was used without further purification.

Step 3: Preparation of Example 83 and Example 84

The two diastereomers, Example 83 and Example 84 were synthesized in thesame manner as Example 18 using trans(±)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid andExample 5. The two diastereomers were separated by a supercritical fluidchromatography (Chiralpak AD-H, 5 μM, 21×250 mm, 50% MeOH, flow 65mL/min, 100 bar).

Example 83 (Less Polar Fraction)

¹H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H), 7.55-7.24 (m,3H), 7.24-7.02 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.01 (d, J=2.0 Hz, 1H),5.85 (qd, J=15.8, 9.5 Hz, 2H), 4.19-3.82 (m, 5H), 3.84-3.36 (m, 6H),3.34 (s, 3H), 3.21-3.00 (m, 2H), 2.93-2.67 (m, 3H), 2.46 (dt, J=10.6,5.6 Hz, 3H), 2.24 (d, J=8.1 Hz, 2H), 2.15-1.94 (m, 4H), 1.85-1.54 (m,3H), 1.50-1.14 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₆ClN₅O₅S:732.29; found:732.00.

Example 84 (More Polar Fraction)

¹H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J=8.8 Hz, 1H), 7.31 (d, J=2.0Hz, 1H), 7.25 (dd, J=8.2, 1.8 Hz, 1H), 7.18 (dd, J=8.4, 2.4 Hz, 1H),7.15 (d, J=2.0 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H),6.11 (dt, J=15.5, 6.4 Hz, 1H), 5.98 (d, J=2.0 Hz, 1H), 5.61 (dd, J=15.4,9.0 Hz, 1H), 4.19-4.12 (m, 1H), 4.01 (dd, J=21.8, 11.8 Hz, 2H),3.94-3.85 (m, 5H), 3.74-3.66 (m, 3H), 3.50 (p, J=1.6 Hz, 1H), 3.34-3.31(m, 2H), 3.27 (s, 3H), 3.15 (p, J=1.6 Hz, 1H), 3.08-3.01 (m, 1H),2.88-2.74 (m, 3H), 2.56-1.70 (m, 10H), 1.59-1.54 (m, 1H), 1.46-1.39 (m,1H), 1.18-1.36 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₆ClN₅O₅S:732.29; found: 732.06.

Example 85

Example 85 was synthesized in the same manner as Example 18 using4-(1H-pyrazol-1-yl)butanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.64 (d, J=2.3 Hz,1H), 7.48 (dd, J=1.9, 0.7 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H), 7.32 (dd,J=8.3, 1.9 Hz, 1H), 7.21-7.04 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 6.27 (t,J=2.1 Hz, 1H), 5.97-5.74 (m, 2H), 4.20 (t, J=6.8 Hz, 2H), 4.12-3.88 (m,3H), 3.74 (dd, J=26.9, 14.7 Hz, 2H), 3.66-3.47 (m, 2H), 3.38 (d, J=32.3Hz, 4H), 3.10 (dd, J=15.0, 10.9 Hz, 1H), 2.93-2.60 (m, 3H), 2.61-2.30(m, 4H), 2.31-1.71 (m, 12H), 1.41 (t, J=13.2 Hz, 1H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₈H₄₆ClN₅O₅S: 720.29; found:720.97.

Example 86

Example 86 was synthesized in the same manner as Example 18 using2-(imidazo[1,2-a]pyridin-2-yl)acetic acid instead of 3-methoxypropionicacid. LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₄₄ClN₅O₅S: 742.28; found:742.10.

Example 87

Example 87 was synthesized in the same manner as Example 18 usingExample 5 and 3-(2-(trifluoromethyl)phenyl)propanoic acid instead of3-methoxypropionic acid. LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₁H₄₅ClF₃N₃O₅S: 784.2793; found: 784.392.

Example 88

Example 88 was synthesized in the same manner as Example 18 using3-(furan-2-yl)propanoic acid instead of 3-methoxypropionic acid. ¹H NMR(400 MHz, Chloroform-d) δ 7.70 (d, J=8.5 Hz, 1H), 7.34-7.29 (m, 2H),7.22 (d, J=1.9 Hz, 1H), 7.12 (dd, J=8.2, 2.2 Hz, 1H), 7.07 (d, J=2.3 Hz,2H), 6.92 (d, J=8.2 Hz, 2H), 5.85 (dt, J=15.5, 5.2 Hz, 1H), 5.69 (dd,J=15.8, 7.9 Hz, 1H), 4.12-3.95 (m, 2H), 3.60 (dd, J=7.8, 3.4 Hz, 1H),3.30 (d, J=1.9 Hz, 3H), 3.08-2.94 (m, 4H), 2.82-2.64 (m, 6H), 2.30 (td,J=14.7, 13.8, 6.2 Hz, 4H), 2.06-1.64 (m, 12H). LCMS-ESI+ (m/z): calcdfor C₃₈H₄₄ClN₃O₆S: 706.2712; found: 706.305.

Example 89

Preparation of 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic Acid Step 1

Sodium hydride (70 mg, 3 mmol) was dissolved in THF (6 mL) and thencooled to 0° C. then ethyl 2-(dimethoxyphosphoryl)acetate (650 mg, 3mmol) was added to the mixture and stirred for 20 min. Then1,3-dimethyl-1H-pyrazole-5-carbaldehyde (300 mg. 2.417 mmol) was addedto the reaction and was warmed to room temperature for 30 min. After thereaction was complete by TLC the contents were diluted with ethylacetate and aqueous ammonium chloride and then the organic layer wasdried over MgSO₄, filtered and concentrated. Then the crude reactionmixture was purified on silica gel chromatography in a 2/1 hexane ethylacetate to yield ethyl (E)-3-(1,3-dimethyl-1H-pyrazol-5-yl)acrylate (405mg) LCMS-ESI+ (m/z): calcd for C₁₀H₁₄N₂O₂: 195.113; found: 195.132.

Step 2

Ethyl (E)-3-(1,3-dimethyl-1H-pyrazol-5-yl)acrylate (405 mg, 2 mmol) wascharged to reaction flask in ethanol (7 mL). Then palladium on carbonwas added and the reaction was stirred and the contents were purged andevacuated with nitrogen. Then hydrogen gas from a balloon was added andthe reaction was stirred for 3 hours. LCMS indicated complete conversionto the hydrogenated product. Then the contents were filtered through afritted funnel and diluted with ethyl acetate. The palladium frit waswetted with water. The contents were concentrated and the product wascarried to the next step without further purification to yield ethyl3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoate. LCMS-ESI+ (m/z): [M+H] calcdfor C₁₀H₁₇N₂O₂: 197.129; found: 197.090.

Step 3

Ethyl 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoate (404 mg, 2 mmol) wasdissolved in THF (2 mL), ethanol (1 mL) and water (1 mL) then sodiumhydroxide (412 mg, 10 mmol) was added. The reaction was then stirred for1 hour. LCMS indicated complete conversion. The reaction was dilutedwith DCM and then acidified to pH 4 with 1N HCl. Then the organic layerwas dried over MgSO₄ and concentrated to yield3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid. LCMS-ESI+ (m/z): [M+H]calcd for C8H₁₃N₂O₂: 169.0972; found: 169.082.

Preparation of Example 89

Example 89 was synthesized in the same manner as Example 18 using3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid instead of3-methoxypropionic acid. ¹H NMR (400 MHz, Chloroform-d) δ 7.55-7.46 (m,2H), 7.23 (d, J=8.2 Hz, 1H), 7.02 (d, J=2.6 Hz, 2H), 6.94 (d, J=8.2 Hz,1H), 6.69 (d, J=8.4 Hz, 1H), 5.77 (d, J=7.5 Hz, 2H), 3.99 (s, 3H), 3.89(d, J=15.3 Hz, 1H), 3.65 (t, J=12.8 Hz, 2H), 3.56-3.50 (m, 1H), 3.39 (d,J=14.3 Hz, 1H), 3.35 (s, 3H), 3.11-2.98 (m, 2H), 2.96-2.84 (m, 2H),2.84-2.60 (m, 4H), 2.51-2.35 (m, 2H), 2.31-2.22 (m, 2H), 2.11 (d, J=8.7Hz, 2H), 2.08 (s, 3H), 1.99 (d, J=17.1 Hz, 4H), 1.89-1.73 (m, 3H),1.36-1.20 (m, 3H). LCMS-ESI+ (m/z): [M+H] calcd for C₃₉H₄₈ClN₅O₅S:734.3137; found: 734.400.

Example 90

Example 90 was synthesized in the same manner as Example 18 using3-(4-chlorophenyl)propanoic acid instead of 3-m ethoxy propionic acid.LCMS-ESI+ (m/z): [M+H] calcd for C₃₉H₄₅Cl₂N₃O₅S: 750.253; found:750.976.

Example 91

Example 91 was synthesized in the same manner as Example 18 using3-(thiazol-2-yl)propanoic acid instead of 3-methoxypropionic acid. ¹HNMR (400 MHz, Chloroform-d) δ 7.88 (d, J=3.6 Hz, 1H), 7.70-7.64 (m, 1H),7.40 (d, J=3.5 Hz, 1H), 7.24 (d, J=1.9 Hz, 1H), 7.18-7.14 (m, 2H),7.09-7.04 (m, 2H), 6.92 (d, J=8.2 Hz, 1H), 5.91-5.62 (m, 2H), 4.09-3.96(m, 2H), 3.84-3.67 (m, 3H), 3.62-3.52 (m, 3H), 3.30 (s, 3H), 3.11-2.95(m, 3H), 2.82-2.71 (m, 2H), 2.45-2.23 (m, 4H), 2.09-1.99 (m, 2H), 1.94(q, J=9.6 Hz, 4H), 1.88-1.64 (m, 4H), 1.27 (d, J=9.8 Hz, 2H). LCMS-ESI+(m/z): [M+H] calcd for C₃₇H₄₃ClN₄O₅S₂: 723.2436; found: 723.971.

Example 92

Preparation of 3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propanoicAcid Step 1

(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)methanol (750 mg, 4.16 mmol)was charged into a round bottom flask and then was dissolved in DCM (10mL). Then Dess Martin Periodinane (2.2 g, 5 mmol) was added. Thereaction was allowed to stir for 45 min. Then LCMS indicated completionof the reaction the contents were diluted with sodium bicarbonateaqueous solution and then the organic layer was dried over MgSO₄ andthen filtered and concentrated. The crude material was purified bysilica gel chromatography in 1/1 hexane ethyl acetate to yield1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carbaldehyde. LCMS-ESI+ (m/z):[M+H] calcd for C₆H₅F₃N₂O: 179.043; found: 179.016.

Step 2-4

3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propanoic acid wassynthesized in the same manner as3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid in Example 90 (Step 1-3).

Preparation of Example 92

Example 92 was synthesized in the same manner as Example 18 using3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propanoic acid instead of3-methoxypropionic acid. ¹H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J=2.1Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.10-6.99 (m, 2H), 6.95 (d, J=8.4 Hz,1H), 6.71 (d, J=8.3 Hz, 1H), 6.28 (d, J=2.1 Hz, 1H), 5.78 (d, J=7.3 Hz,2H), 4.91 (q, J=8.3 Hz, 2H), 3.94 (s, 3H), 3.72-3.58 (m, 3H), 3.58-3.53(m, 1H), 3.36 (s, 3H), 3.09-2.91 (m, 4H), 2.88-2.66 (m, 4H), 2.44 (s,2H), 2.33-2.21 (m, 3H), 2.04-1.91 (m, 4H), 1.89-1.74 (m, 4H), 1.33-1.21(m, 2H). LCMS-ESI+ (m/z): [M+H] calcd for C₃₉H₄₅ClN₅O₅S₂: 788 0.2855;found: 788.261.

Example 93

Example 93 was synthesized in the same manner as Example 18 using3-(4-methylthiazol-5-yl)propanoic acid instead of 3-methoxypropionicacid. LCMS-ESI+ (m/z): [M+H] calcd for C₃₈H₄₅ClN₄O₅S₂: 737.2593; found:737.220.

Example 94

Example 94 was synthesized in the same manner as Example 18 using4,4,4-trifluorobutanoic acid instead of 3-methoxypropionic acid. ¹H NMR(400 MHz, Chloroform-d) δ 7.64 (d, J=8.5 Hz, 1H), 7.20-7.04 (m, 3H),7.03-6.97 (m, 1H), 6.94 (d, J=8.5 Hz, 1H), 5.91-5.64 (m, 2H), 4.01 (q,J=12.0 Hz, 3H), 3.73 (dd, J=31.3, 14.6 Hz, 3H), 3.59 (dd, J=8.1, 3.2 Hz,1H), 3.31 (s, 3H), 3.18 (dt, J=12.1, 6.0 Hz, 1H), 3.02 (dd, J=15.2, 10.7Hz, 1H), 2.80-2.63 (m, 4H), 2.59-2.46 (m, 2H), 2.39-2.27 (m, 3H),2.08-1.90 (m, 5H), 1.88-1.78 (m, 2H), 1.76-1.65 (m, 2H), 0.98-0.77 (m,2H). LCMS-ESI+ (m/z): [M+H] calcd for C₃₅H₄₁ClF₃N₃O₅S: 708.248; found:708.865.

Example 95

Example 95 was synthesized in the same manner as Example 18 using5,5,5-trifluoropentanoic acid instead of 3-methoxypropionic acid. ¹H NMR(400 MHz, Chloroform-d) δ 7.61 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.3 Hz,1H), 7.14 (s, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.94 (dd, J=8.6, 4.0 Hz, 2H),5.89-5.66 (m, 2H), 3.99 (q, J=11.8 Hz, 2H), 3.72 (dd, J=29.4, 14.8 Hz,3H), 3.57 (dd, J=7.6, 3.1 Hz, 1H), 3.32 (s, 3H), 3.02 (dd, J=15.1, 10.9Hz, 1H), 2.80-2.67 (m, 3H), 2.65-2.53 (m, 2H), 2.46-2.14 (m, 7H), 1.97(dq, J=14.9, 7.4 Hz, 6H), 1.86-1.67 (m, 4H), 1.33 (t, J=12.9 Hz, 2H).LCMS-ESI+ (m/z): [M+H] calcd for C₃₆H₄₃ClF₃N₃O₅S: 722.264; found:722.274.

Example 96

Example 96 was synthesized in the same manner as Example 18 using2-phenoxyacetic acid instead of 3-methoxypropionic acid. ¹H NMR (400MHz, chloroform-d) δ 7.73 (d, J=8.3 Hz, 1H), 7.50-7.27 (m, 4H), 7.18(dd, J=8.5, 2.2 Hz, 1H), 7.12-6.97 (m, 4H), 6.93 (dd, J=8.2, 2.8 Hz,1H), 5.95-5.65 (m, 2H), 4.10 (d, J=12.0 Hz, 1H), 4.04-3.91 (m, 2H),3.91-3.83 (m, 1H), 3.75 (q, J=14.1, 13.1 Hz, 2H), 3.61 (dd, J=7.7, 3.4Hz, 1H), 3.28 (s, 3H), 3.24-3.16 (m, 1H), 3.07-2.94 (m, 1H), 2.84-2.61(m, 3H), 2.46-2.23 (m, 3H), 2.08-1.56 (m, 8H), 1.44-1.29 (m, 3H), 0.88(t, J=8.1 Hz, 1H). LCMS-ESI+ (m/z): [M+H] calcd for C₃₉H₄₄ClN₃O₆S:718.271; found: 718.109.

Example 97

Example 97 was synthesized in the same manner as Example 18 using3-phenylpropanoic acid instead of 3-methoxypropionic acid. ¹H NMR (400MHz, chloroform-d) δ 7.67 (dd, J=14.8, 8.6 Hz, 1H), 7.34-7.27 (m, 3H),7.25-7.16 (m, 4H), 7.10-7.00 (m, 2H), 6.91 (d, J=8.3 Hz, 1H), 5.95-5.56(m, 2H), 4.09-3.94 (m, 2H), 3.88 (q, J=14.4, 11.1 Hz, 1H), 3.74 (dd,J=25.2, 14.8 Hz, 3H), 3.59 (dd, J=7.9, 3.3 Hz, 1H), 3.33 (s, 3H),3.08-2.91 (m, 3H), 2.86-2.51 (m, 5H), 2.48-2.23 (m, 2H), 2.24-2.14 (m,1H), 2.04 (t, J=10.7 Hz, 2H), 1.98-1.63 (m, 6H), 1.41-1.23 (m, 2H), 0.86(t, J=10.0 Hz, 1H). LCMS-ESI+ (m/z): [M+H] calcd for C₄₀H₄₆ClN₃O₅S:716.292; found: 716.069.

Example 98

Example 98 was synthesized in the same manner as Example 18 using1-methyl-1H-indole-2-carboxylic acid instead of 3-methoxypropionic acid.LCMS-ESI+ (m/z): [M+H] calcd for C₄₁H₄₅ClN₄O₅S: 741.287; found: 741.886.

Example 99

Example 99 was synthesized in the same manner as Example 18 using3-(2-methylthiazol-4-yl)propanoic acid instead of 3-methoxypropionicacid. ¹H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J=8.2 Hz, 1H), 7.38 (dd,J=25.3, 8.7 Hz, 1H), 7.23 (s, 1H), 7.21-7.13 (m, 2H), 7.08 (s, 1H), 6.90(d, J=8.2 Hz, 1H), 5.97-5.63 (m, 2H), 4.09 (d, J=12.1 Hz, 1H), 4.01 (t,J=10.3 Hz, 1H), 3.84 (t, J=14.5 Hz, 1H), 3.73 (s, 3H), 3.60 (d, J=7.4Hz, 1H), 3.27 (d, J=3.9 Hz, 3H), 3.06-2.91 (m, 1H), 2.78 (s, 2H), 2.65(s, 2H), 2.28 (d, J=31.5 Hz, 4H), 2.07-1.60 (m, 8H), 1.43-1.12 (m, 6H),0.94-0.72 (m, 2H). LCMS-ESI+ (m/z): [M+H] calcd for C₃₈H₄₅ClN₄O₅S₂:737.295; found: 737.040.

Example 100

Preparation of 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic Acid Step 1

1-Methyl-1H-pyrazol-5-ol (250 mg, 3 mmol) was charged into a roundbottom flask and then potassium carbonate (387 mg, 3 mmol) was added.Then THF (5 mL) was added. Ethyl bromoacetate (547 mg, 3 mmol) was addedthen the reaction was stirred at 50° C. for 1 hour. TLC indicatedconsumption of 1-methyl-1H-pyrazol-5-ol. The contents were then dilutedwith ethyl acetate and water, and then the organic layer was dried overMgSO₄ filtered and concentrated to yield ethyl2-((1-methyl-1H-pyrazol-5-yl)oxy)acetate.

Step 2

Ethyl 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetate (0.265 mg, 1.44 mmol) wasthen diluted in THF (2 mL) water (1 mL) and ethanol (1 mL) then sodiumhydroxide (115 mg, 2.88 mmol) was added. The reaction was stirred for 2hours and then dilute with sec-butanol and 1N HCl to pH˜4 and theorganic layer was dried over MgSO₄ filtered and concentrated to yield2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic acid. LCMS-ESI+ (m/z): [M+H]calcd for C₆H₈N₂O₃: 157.061; found: 157.088.

Preparation of Example 100

Example 100 was synthesized in the same manner as Example 18 using2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic acid instead of3-methoxypropionic acid. ¹H NMR (400 MHz, acetone-d6) δ 7.77 (d, J=8.6Hz, 1H), 7.43 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.22 (dd, J=8.5, 2.3 Hz,1H), 7.11 (d, J=2.4 Hz, 2H), 7.04 (s, 1H), 6.88 (d, J=8.2 Hz, 1H),5.96-5.78 (m, 2H), 4.13-3.92 (m, 4H), 3.79 (dd, J=23.4, 14.6 Hz, 2H),3.63 (dd, J=13.4, 7.6 Hz, 1H), 3.53 (dd, J=7.7, 3.0 Hz, 1H), 3.45 (d,J=14.4 Hz, 1H), 3.26 (s, 3H), 3.04 (t, J=7.2 Hz, 2H), 2.90-2.80 (m, 2H),2.62 (s, 3H), 2.46 (d, J=7.2 Hz, 2H), 2.34-2.18 (m, 2H), 2.01-1.91 (m,5H), 1.84-1.70 (m, 3H), 1.57-1.39 (m, 2H). LCMS-ESI+ (m/z): [M+H] calcdfor C₃₇H₄₄ClN₅O₆S: 722.277; found: 722.907.

Example 101

Example 101 was synthesized in the same manner as Example 18 using3-(5-methylthiazol-4-yl)propanoic acid instead of 3-methoxypropionicacid. LCMS-ESI+ (m/z): [M+H] calcd for C₃₈H₄₅ClN₄O₅S₂: 737.2953; found:737.894.

Example 102

Example 102 was synthesized in the same manner as Example 18 using3-(5-methyl-1,3,4-thiadiazol-2-yl)propanoic acid (prepared in the samemanner as 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid as Example 89from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde). ¹H NMR (400 MHz,chloroform-d) δ 7.64 (d, J=8.5 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.15 (s,1H), 7.06 (d, J=2.3 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.93 (d, J=8.3 Hz,1H), 5.91-5.64 (m, 2H), 4.01 (q, J=12.1 Hz, 2H), 3.89 (s, 1H), 3.83-3.65(m, 3H), 3.59 (dd, J=8.2, 3.1 Hz, 1H), 3.50-3.35 (m, 2H), 3.32 (s, 3H),3.04 (dd, J=16.7, 9.6 Hz, 3H), 2.78 (s, 3H), 2.76-2.62 (m, 3H),2.47-2.22 (m, 4H), 2.09-1.91 (m, 4H), 1.81 (p, J=9.9 Hz, 2H), 1.71 (t,J=9.3 Hz, 1H), 1.43-1.14 (m, 3H). LCMS-ESI+ (m/z): [M+H] calcd forC₃₇H₄₄ClN₅O₅S₂: 738.255; found: 738.054.

Example 103

Example 103 was synthesized in the same manner as Example 18 using3-(1,4-Dimethyl-1H-pyrazol-5-yl)propanoic acid (prepared in the samemanner as 3-(1,3-dimethyl-1H-pyrazol-5-yl)propanoic acid in Example 89from 5-methyl-1,3,4-thiadiazole-2-carbaldehyde). NMR (400 MHz,chloroform-d) δ 7.54 (d, J=7.0 Hz, 2H), 7.22 (d, J=7.3 Hz, 1H),7.14-6.99 (m, 2H), 6.94 (d, J=8.2 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H),5.90-5.66 (m, 2H), 4.06-3.94 (m, 4H), 3.85 (s, 1H), 3.66 (dd, J=22.7,14.0 Hz, 2H), 3.58-3.50 (m, 1H), 3.37 (d, J=23.2 Hz, 3H), 3.04 (t,J=12.4 Hz, 2H), 2.99-2.65 (m, 5H), 2.40 (d, J=19.5 Hz, 2H), 2.24 (d,J=11.3 Hz, 2H), 2.11 (s, 2H), 2.09 (s, 3H), 1.99 (d, J=12.9 Hz, 4H),1.90-1.65 (m, 3H), 1.37-1.20 (m, 3H), 0.80 (dd, J=55.2, 11.8 Hz, 1H).LCMS-ESI+ (m/z): [M+H] calcd for C₃₉H₄₈ClN₅O₅S: 734.314; found: 734.132.

Example 104

Example 104 was synthesized in the same manner as Example 18 using1-ethyl-1H-pyrazole-4-carboxylic acid instead of 3-methoxypropionicacid. ¹H NMR (400 MHz, methanol-d4) δ 8.43 (s, 1H), 7.93 (s, 1H), 7.65(d, J=8.5 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.26 (s, 1H), 7.06 (s, 1H),6.93 (dd, J=13.2, 8.6 Hz, 2H), 5.97-5.78 (m, 2H), 4.22 (q, J=7.3 Hz,2H), 3.98 (d, J=15.3 Hz, 3H), 3.83-3.62 (m, 2H), 3.58 (dd, J=8.3, 2.9Hz, 1H), 3.52-3.40 (m, 2H), 3.35 (s, 3H), 3.19-2.99 (m, 2H), 2.86-2.68(m, 3H), 2.49 (s, 2H), 2.37-2.24 (m, 2H), 2.08 (d, J=12.7 Hz, 3H), 1.94(s, 3H), 1.83 (t, J=6.7 Hz, 2H), 1.46 (t, J=7.3 Hz, 3H). LCMS-ESI+(m/z):calcd for H+C₃₇H₄₄ClN₅O₅S: 706.22824; found: 706.194.

Example 105

Example 105 was synthesized in the same manner as Example 18 using2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid instead of3-methoxypropionic acid. 1H NMR (400 MHz, chloroform-d) δ 7.73 (d, J=8.5Hz, 1H), 7.41 (dd, J=8.3, 1.8 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.16 (dd,J=8.5, 2.3 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 5.86(dt, J=15.8, 5.2 Hz, 1H), 5.73 (dd, J=15.9, 7.5 Hz, 1H), 4.15 (s, 2H),4.12-3.92 (m, 4H), 3.92-3.63 (m, 4H), 3.55 (dddd, J=20.5, 11.9, 6.3, 3.2Hz, 3H), 3.32-3.25 (m, 4H), 3.01 (dd, J=14.9, 11.0 Hz, 1H), 2.84-2.66(m, 3H), 2.50-2.18 (m, 4H), 2.14-1.56 (m, 12H), 1.47-1.18 (m, 2H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₈ClN₃O₇S: 726.29; found: 726.22.

Example 106

Step 1

N′-(tert-butyldimethylsilyl)hex-5-ene-1-sulfonimidamide was prepared inthe same manner as Example 1 (step 4 and step 5) using(S)-2-methylpent-4-ene-1-sulfonamide instead of(2R,3S)-3-methylhex-5-ene-2-sulfonamide. ¹H NMR (400 MHz, Chloroform-d)δ 5.75 (ddt, J=19.5, 9.5, 7.0 Hz, 1H), 5.06 (d, J=1.4 Hz, 1H), 5.03 (dq,J=5.1, 1.7 Hz, 1H), 4.75 (d, J=7.7 Hz, 2H), 3.13 (ddd, J=18.6, 13.7, 4.6Hz, 1H), 2.91 (ddd, J=22.5, 13.8, 7.1 Hz, 1H), 2.32-2.16 (m, 2H),2.16-2.02 (m, 2H), 1.10 (dd, J=6.6, 4.2 Hz, 3H), 0.88 (s, 9H), 0.10 (d,J=3.0 Hz, 6H).

Step 2: Preparation of Intermediate 106-2

To a stirred solution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonylchloride (1.56 g, 3.11 mmol) in acetonitrile (30 mL) was addedpyridazine (0.22 ml, 3.11 mmol) in acetonitrile (6 mL), followed by(2S)—N′-(tert-butyldimethylsilyl)-2-methylpent-4-ene-1-sulfonimidamide(0.9 g, 3.27 mmol) in acetonitrile (6 mL). The resulting mixture wasstirred at rt overnight. The reaction mixture was concentrated and theresidue was purified by silica gel column (0-50% EtOAc in hexanes).

Step 3: Preparation of Intermediate 106-3

To a stirred solution of intermediate 106-2 (1.54 g, 2.46 mmol) inCH₂Cl₂ (15 mL) was added triethylamine (0.69 mL, 4.92 mmol) in an icebath, followed by di-tert-butyl dicarbonate (0.81 g, 3.69 mmol) and4-(dimethylamino)-pyridine (120.17 mg, 0.98 mmol). The resulting mixturewas stirred at rt for 3 h. The reaction mixture was concentrated and theresidue was purified by silica gel column. The fraction wasconcentrated, dissolved in EtOAc and washed with 1% HCl solution, thenwashed with saturated aqueous NaHCO₃ solution. The organic phase wasdried over MgSO₄, filtered, concentrated and the residue was purifiedagain by silica gel column to give the desired product.

Step 4: Preparation of Intermediate 106-4

The reaction mixture intermediate 106-3 (330 mg, 0.45 mmol),Hoveyda-Grubbs 2^(nd) generation catalyst (85.18 mg, 0.14 mmol) in1,2-dichloroethane (150 mL) was degassed with argon. The reactionmixture was stirred at 60° C. overnight. The reaction mixture wasconcentrated and the residue was purified by silica gel column. Twodiastereomers were isolated (the less polar product is 106-4).

Step 5: Preparation of Example 106

Example 106 was synthesized in the same manner as Example 18 using2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid (3.61 mg, 0.023 mmol)instead of 3-methoxypropionic acid and the less polar diastereomerintermediate 106-4 (9 mg, 0.015 mmol). ¹H NMR (400 MHz, Methanol-d4) δ7.76 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz,1H), 7.15-7.06 (m, 2H), 6.91 (d, J=8.2 Hz, 1H), 6.10 (dt, J=14.7, 7.0Hz, 1H), 5.63 (dd, J=15.3, 8.4 Hz, 1H), 4.22 (s, 2H), 4.15 (dd, J=14.8,6.9 Hz, 1H), 4.11-4.01 (m, 2H), 4.00-3.92 (m, 2H), 3.92-3.81 (m, 2H),3.77 (d, J=8.0 Hz, 1H), 3.71 (td, J=10.0, 9.4, 4.9 Hz, 2H), 3.53-3.45(m, 2H), 3.29 (s, 3H), 3.07 (dd, J=15.1, 9.7 Hz, 2H), 2.93-2.69 (m, 3H),2.48 (d, J=21.0 Hz, 3H), 2.37-2.06 (m, 4H), 2.06-1.88 (m, 4H), 1.88-1.73(m, 3H), 1.65 (dtt, J=13.4, 9.0, 4.3 Hz, 2H), 1.45 (t, J=12.1 Hz, 1H),1.15 (d, J=6.8 Hz, 3H). LCMS-ESI+: calc'd for C₃₉H₅₀ClN₃O₇S: 740.3(M+H); found: 740.0 (M+H).

Example 107

Example 107 was synthesized in the same manner as Example 75 usingintermediate 106-4 from Example 106 and cyclopropylmethanamine. 1H NMR(400 MHz, methanol-d4) δ 7.73 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H),7.12 (d, J=11.4 Hz, 2H), 7.02 (s, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.06 (dd,J=14.6, 7.3 Hz, 1H), 5.60 (dd, J=15.3, 8.8 Hz, 1H), 4.25 (dd, J=14.9,6.7 Hz, 1H), 4.11-3.99 (m, 2H), 3.84 (d, J=15.1 Hz, 2H), 3.78 (dd,J=8.9, 3.5 Hz, 1H), 3.67 (d, J=14.2 Hz, 1H), 3.28 (s, 3H), 3.13-3.01 (m,3H), 2.88-2.69 (m, 2H), 2.46 (dt, J=23.9, 13.6 Hz, 3H), 2.18 (ddd,J=36.0, 20.5, 10.7 Hz, 3H), 1.99-1.89 (m, 3H), 1.79 (dt, J=17.4, 9.2 Hz,3H), 1.43 (t, J=11.9 Hz, 1H), 1.31 (s, 1H), 1.14 (d, J=6.6 Hz, 3H),1.08-0.97 (m, 1H), 0.57-0.47 (m, 2H), 0.25 (dt, J=5.9, 4.4 Hz, 2H).LCMS-ESI+: calc'd for C₃₇H₄₇ClN₄O₅S: 695.3 (M+H); found: 694.8 (M+H).

Example 108

Example 108 was synthesized in the same manner as Example 18 using2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid instead of3-methoxypropionic acid and intermediate 49-3. ¹H NMR (400 MHz,methanol-d4) δ 7.75 (d, J=8.4 Hz, 1H), 7.19 (dd, J=8.4, 2.4 Hz, 1H),7.16-7.12 (m, 2H), 7.00 (s, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.00-5.93 (m,1H), 5.59 (dd, J=15.2, 9.2 Hz, 1H), 4.38-4.32 (m, 1H), 4.18 (s, 2H),4.00-3.93 (m, 2H), 3.83 (d, J=14.8 Hz, 1H), 3.76-3.65 (m, 3H), 3.52-3.45(m, 3H), 3.37-3.34 (m, 3H), 3.24 (s, 3H), 3.16-3.06 (m, 1H), 2.86-2.73(m, 3H), 2.49-1.72 (m, 12H), 1.67-1.58 (m, 2H), 1.54 (d, J=6.8 Hz, 3H),1.50-1.42 (m, 1H), 1.14 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₄₀H₅₂ClN₃O₇S: 754.4; found: 754.2.

Example 109 Method 1

Step 1

(4S)-5-[S-amino-N-[tert-butyl(dimethyl)silyl]sulfonimidoyl]-4-methyl-pent-1-ene(106-1, 14.9 g, 53.9 mmol) was azeotroped with anhydrous toluene (3×50mL) and dissolved in anhydrous tetrahydrofuran (250 mL) under anatmosphere of argon. The solution was cooled to −50° C. (internaltemperature probe). A solution of 2.5 M n-BuLi in hexanes (46.3 mL, 116mmol) was added dropwise over 5 min. This mixture was left to stir for15 min. Concurrently (4-nitrophenyl) [(1S)-1-phenylethyl] carbonate(5-3-1, 20.1 g, 70.1 mmol) was azeotroped with toluene (3×50 mL). Thematerial was taken up in anhydrous tetrahydrofuran (50 mL) under anatmosphere of argon. The solution was added to the reaction via cannulaover 5 min. The reaction was initially yellow but turned very dark(green). After 15 min the reaction was warmed to 0° C. (ice bath). Thereaction turned yellow while warming. After 1 h, TLC (20% ethylacetate/hexanes visualized with KMnO₄ stain) showed the reaction wascomplete. The reaction was quenched with water (150 mL) at 0° C. Ethylacetate (150 mL) was added. The phases were separated and the aqueousphase was extracted with ethyl acetate (2×75 mL). The combined organicphases were washed with sat NaHCO₃ (150 mL) and brine (150 mL). Theorganic phase was dried over sodium sulfate and the solvent was removedunder reduced pressure, providing, crude [(1S)-1-phenylethyl]N—[N-[tert-butyl(dimethyl)silyl]-S-[(2S)-2-methylpent-4-enyl]sulfonimidoyl]carbamate(109-1-1).

Step 2

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M,63.6 mL, 63.6 mmol) was added to a solution of the 109-1-1 (22.5 g, 53.0mmol) in anhydrous tetrahydrofuran at 0° C. After 90 min at 0° C., thereaction was complete. The solvent was removed under reduced pressure.The residue was diluted with water (150 mL) and ethyl acetate (150 mL).The phases were separated and the aqueous phase was extracted with ethylacetate (3×100 mL). The combined organic phases were washed with brineand dried over sodium sulfate. The solvent was removed pressure and theresidue was subjected to flash chromatography (0-65% ethylacetate/hexanes 120 g gold Teledyne ISCO column with solid loading). Anevaporative light scattering detector (ELSD) along with UV was used forpeak detection. The fractions containing product were combined and thesolvent was removed under reduced pressure to give((2S)-2-methylpent-4-en-1-ylsulfonimidoyl)carbamate as a mixture ofdiastereomers at sulfur. The solids were subjected to chiral SFCseparation, with ethanol as a co-solvent using a ChiralPak IC column.Alternatively, methanol was used as a co-solvent on a ChiralPak AD-Hcolumn. Fractions containing the same diastereomer were combined and thesolvent was removed under reduced pressure, providing (S)-1-phenylethyl((2S)-2-methylpent-4-en-1-ylsulfonimidoyl)carbamate as twodiastereomers.

The first eluted diasteromer (109-1-2, Rt=3.05 min on ChiralPak IC with15% ethanol co-solvent, absolute stereochemistry tentatively assigned asdrawn): ¹H NMR (400 MHz, chloroform-d) δ 7.43-7.33 (m, 4H), 7.33-7.29(m, 1H), 5.74 (q, J=6.7 Hz, 1H), 5.62 (ddt, J=16.0, 11.0, 7.1 Hz, 1H),5.05 (d, J=1.3 Hz, 1H), 5.04-4.99 (m, 1H), 3.43 (dd, J=14.4, 4.5 Hz,1H), 3.06 (dd, J=14.4, 7.9 Hz, 1H), 2.30-2.20 (m, 1H), 2.20-2.04 (m,2H), 1.59 (d, J=6.7 Hz, 3H), 1.14 (d, J=6.7 Hz, 3H).

The second eluted diasteromer (109-1-3, Rt=4.92 min on ChiralPak IC with15% ethanol co-solvent, absolute stereochemistry tentatively assigned asdrawn): ¹H NMR (400 MHz, chloroform-d) δ 7.44-7.32 (m, 4H), 7.32-7.30(m, 1H), 5.79-5.73 (m, 1H), 5.73-5.66 (m, 1H), 5.16-5.05 (m, 2H), 3.38(dd, J=14.5, 4.4 Hz, 1H), 3.20 (dd, J=14.4, 7.7 Hz, 1H), 2.27 (dq,J=12.5, 6.8 Hz, 1H), 2.22-2.10 (m, 2H), 1.59 (d, J=6.7 Hz, 3H), 1.14 (d,J=6.7 Hz, 3H).

Step 3

i) Preparation of (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl) methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (109-1-4): Methyl(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate, 1-3 (11.2 g, 22.5 mmol) wasstirred in 2 N aq NaOH (10 mL) and a mixture of MeOH/THF (1/1) (200 mL)at 60° C. overnight. After cooling, the mixture was neutralized with HCland concentrated. The resulting solid was suspended in water and thenextracted with DCM. The organic phase was dried over anhydrous magnesiumsulfate and the solvent removed under reduced pressure to give 109-1-4which was further used without purification. LCMS-ESI+ (m/z): [M+H]+calcd for C₂₈H₃₂ClNO₄: 482.20; found: 482.14.

ii) Preparation of intermediate 109-1-5: To a stirred solution ofintermediate 109-1-4 (9.68 g, 20.1 mmol) in DCM (200 mL) was addedintermediate 109-1-2 (first eluting diasteromer) (6.17 g, 19.9 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (7.62 g, 39.75 mmol)and 4-(dimethylamino)pyridine (4.21 g, 34.46 mmol). The reaction mixturewas stirred at rt overnight. Then the reaction mixture was diluted withDCM, washed with 1 N HCl and brine. The organic phase was dried overMgSO₄, filtered, concentrated to give 109-1-5 which was further usedwithout purification.

Step 4

To a solution of intermediate 109-1-5 (12.7 g, 16.4 mmol) in DCM (130mL), was added TFA (25 mL). The reaction mixture was stirred at rt.After the reaction is finished, the solvent was removed under vacuum.The residue was dissolved in DCM, washed with saturated NaHCO₃ solution.The organic phase was separated, dried over MgSO₄, filtered, andconcentrated to give 109-1-6 which was further used withoutpurification.

Step 5

To a solution of intermediate 109-1-6 (10 g, 15.97 mmol) in DCM, wasadded triethylamine (4.45 mL, 31.94 mmol), 4-(dimethylamino)-pyridine(500 mg, 4.09 mmol) and di-tert-butyl dicarbonate (5.23 g, 23.95 mmol).The reaction mixture was stirred at rt overnight. The reaction mixturewas washed with 1N HCl (aq) and brine. The organic phase was separated,dried over MgSO₄, filtered, concentrated down and purified silica gelcolumn chromatography (0-100% EtOAc/hexanes) to give intermediate109-1-7.

Step 6

Intermediate 109-1-7 (1 g, 1.38 mmol), Hoveyda-Grubbs II (258.13 mg,0.41 mmol) in 1,2-dichloroethane (400 mL) was degassed with argon. Thereaction mixture was stirred at 60° C. overnight. The reaction mixturewas concentrated, and the residue was purified by column chromatography(SiO₂, 0-70% EtOAc/hexanes) to give Example 109. ¹H NMR (400 MHz,chloroform-d) δ 7.76 (d, J=8.5 Hz, 1H), 7.43 (dd, J=8.2, 1.9 Hz, 1H),7.32 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.5, 2.3 Hz, 1H), 7.10 (d, J=2.3 Hz,1H), 6.93 (d, J=8.2 Hz, 1H), 6.27 (ddd, J=15.1, 7.9, 5.2 Hz, 1H), 5.99(s, 2H), 5.56 (dd, J=15.3, 8.2 Hz, 1H), 4.20 (s, 2H), 4.06 (t, J=11.4Hz, 2H), 3.92-3.82 (m, 1H), 3.82-3.69 (m, 2H), 3.47 (d, J=5.6 Hz, 2H),3.36 (d, J=14.6 Hz, 1H), 3.28 (s, 3H), 3.02 (dd, J=15.0, 11.0 Hz, 1H),2.80 (dt, J=11.3, 5.1 Hz, 2H), 2.63-2.53 (m, 1H), 2.47-2.36 (m, 2H),2.26 (dt, J=14.4, 7.3 Hz, 2H), 2.03-1.84 (m, 3H), 1.84-1.57 (m, 4H),1.41 (t, J=13.4 Hz, 1H), 1.16 (d, J=6.1 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₂H₄₀ClN₃O₄S: 598.2; found: 598.1.

Method 2

Step 1

To a solution of intermediate 109-1-3 (second eluting diasteromer fromExample 109-method 1-step 2, 1.1 g, 3.54 mmol) in DCM (50 mL) at 0° C.was added triethylamine (1.48 mL, 10.63 mmol) and trifluoroacetic acidanhydride (1 mL, 7.08 mmol). The reaction mixture was stirred at 0° C.for 30 min. The reaction was quenched with brine. Then the reactionmixture was diluted with DCM, washed with saturated NaHCO₃ solution. Theorganic phase was separated, dried over MgSO₄, filtered, andconcentrated to give intermediate 109-2-1 which was used further withoutpurification.

Step 2

To a solution of intermediate 109-2-1 (1.4 g, 3.44 mmol) in DCM (30 mL)was added TFA (10 mL). The reaction mixture was stirred at rt. Aftercompletion, the reaction mixture was concentrated, and the residue waspurified by silica gel column chromatography (0-50% EtOAc/hexanes) togive intermediate 109-2-2.

Step 3

To a stirred solution of intermediate 109-1-4 (1.5 g, 3.11 mmol) in DCM(200 mL) was added intermediate 109-2-2 (790 mg, 3.06 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (1.5 g, 7.78 mmol) and4-(dimethylamino)pyridine (760 mg, 6.22 mmol). The reaction mixture wasstirred at rt overnight. Then the reaction mixture was diluted with DCM,washed with 1 N HCl and brine. The organic phase was dried over MgSO₄,filtered, concentrated, and the residue was purified by silica gelcolumn chromatography (0-100% EtOAc/hexanes) to give intermediate109-2-3.

Step 4

To a solution of intermediate 109-2-3 (72 mg, 0.1 mmol) in DCE (10 mL)was added TFA (0.02 mL, 0.2 mmol) and Hoveyda-grubbs 2^(nd) generationcatalyst (12.46 mg, 0.02 mmol). The reaction mixture was degassed withargon and then stirred at 60° C. overnight. The reaction mixture wasconcentrated, and the residue was purified by silica gel columnchromatography (0-100% EtOAc/hexanes) to give intermediate 109-2-4.

Step 5

To a solution of intermediate 109-2-4 (130 mg, 0.19 mmol) in MeOH (10mL) and H₂O (2 mL), was added potassium carbonate (129.4 mg, 0.94 mmol).The reaction mixture was stirred at 60° C. overnight. The reactionmixture was concentrated, dissolved in ethyl acetate, washed with water,back extracted with ethyl acetate. The organic phase was separated,dried over MgSO₄, filtered, concentrated, and purified by silica gelcolumn chromatography (0-70% EtOAc/hexanes) to give Example 109.

Method 3 Step 1

To a solution of intermediate 106-1 (690 mg, 2.5 mmol) in THF (10 mL) at−40° C., was added n-butyl lithium (1.6 M in hexanes, 1.87 mL). Theresulting mixture was stirred at −40° C. for 20 min. Then the solutionof (4-nitrophenyl) [(1S)-1-phenylethyl] carbonate (5-3-1, 1.43 g, 4.99mmol) in THF (6 mL) was added dropwise and the reaction mixture wasallowed to warm up to rt and stirred for 3 h. The reaction was quenchedwith water and extracted with EtOAc. The organic layer was separated,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby silica gel column (0-20% EtOAc/hexanes). The two diastereomers wereseparated.

First eluted diasteromer (109-3-1, absolute stereochemistry tentativelyassigned as drawn): ¹H NMR (400 MHz, chloroform-d) δ 7.49-7.29 (m, 5H),5.84 (dq, J=23.2, 6.6 Hz, 1H), 5.74-5.47 (m, 1H), 5.08-4.93 (m, 2H),3.32 (dd, J=14.1, 4.6 Hz, 1H), 3.18-2.95 (m, 1H), 2.29-2.10 (m, 2H),2.03 (ddt, J=13.8, 6.9, 1.3 Hz, 1H), 1.59 (d, J=6.6 Hz, 3H), 1.09 (d,J=6.6 Hz, 3H), 0.93 (s, 9H), 0.21 (d, J=3.1 Hz, 6H).

Second eluted diasteromer (109-3-2, absolute stereochemistry tentativelyassigned as drawn): ¹H NMR (400 MHz, chloroform-d) δ 7.45-7.25 (m, 5H),5.81 (t, J=6.6 Hz, 1H), 5.78-5.63 (m, 1H), 5.11-4.95 (m, 2H), 3.40 (dd,J=13.9, 4.2 Hz, 1H), 3.07 (dd, J=14.0, 7.5 Hz, 1H), 2.27-2.13 (m, 2H),2.13-2.07 (m, 1H), 1.59 (d, J=6.6 Hz, 3H), 1.09 (dd, J=6.7, 3.2 Hz, 3H),0.88 (s, 9H), 0.17-0.09 (m, 6H).

Step 2

To a stirred solution of intermediate 109-3-1 (40 mg, 0.094 mmol) in THF(5 mL) in an ice-bath was added tetrabutylammonium fluoride (1.0 M THF,0.14 ml) slowly. The reaction mixture was stirred at 0° C. for 20 minand then it was slowly warmed up to rt. The reaction mixture was stirredat rt for 2.5 h. The reaction mixture was concentrated, and the residuewas purified by silica gel column (0-60% EtOAc/hexanes) to giveintermediate 109-1-2. 1H NMR (400 MHz, chloroform-d) δ 7.42-7.37 (m,2H), 7.37-7.24 (m, 3H), 5.72 (q, J=6.6 Hz, 1H), 5.62 (ddt, J=15.9, 11.1,7.1 Hz, 1H), 5.51 (s, 2H), 5.07-4.97 (m, 2H), 3.42 (dd, J=14.4, 4.5 Hz,1H), 3.06 (dd, J=14.4, 7.9 Hz, 1H), 2.33-2.01 (m, 3H), 1.57 (d, J=6.7Hz, 3H), 1.12 (d, J=6.8 Hz, 3H).

Method 4

Step 1

Intermediate 109-1-3 was also prepared in similar manner to method3-step 2 (Example 109) using intermediate 109-3-2 instead ofintermediate 109-3-1. Example 109 was synthesized in the same manner asExample 109 (Method 2) using intermediate 109-1-3.

Example 110 Method 1 Step 1

1-[S-amino-N-[tert-butyl(dimethyl)silyl]sulfonimidoyl]hexane (1-5, 5.9g, 20.1 mmol) was azeotroped with anhydrous toluene (3×20 mL) anddissolved in anhydrous tetrahydrofuran (150 mL) under an atmosphere ofargon. The solution was cooled to −50° C. (internal temperature probe).A solution of 2.5 M n-BuLi in hexanes (17.3 mL, 43.3 mmol) was addeddropwise over 5 min. This mixture was left to stir for 15 min.Concurrently (4-nitrophenyl) [(1S)-1-phenylethyl] carbonate (5-3-1, 7.5g, 26.2 mmol) was azeotroped with toluene (3×20 mL). The material wastaken up in anhydrous tetrahydrofuran (60 mL) under an atmosphere ofargon. The solution was added to the reaction via cannula over 5 min.The reaction was initially yellow but turned very dark (green). After 15min, the reaction was warmed to 0° C. (ice bath). The reaction turnedyellow while warming. After 1 h, TLC (20% EtOAc/hexanes visualized withKMnO₄ stain) showed the reaction was complete. The reaction was quenchedwith water (75 mL) at 0° C. EtOAc (50 mL) was added. The phases wereseparated and the aqueous phase was extracted with EtOAc (2×50 mL). Thecombined organic phases were washed with sat NaHCO₃ (75 mL) and brine(75 mL). The organic phase was dried over sodium sulfate and the solventwas removed under reduced pressure, providing crude [(1S)-1-phenylethyl]N—[N-[tert-butyl(dimethyl)silyl]-S-[(1R,2S)-1,2-dimethylpent-4-enyl]sulfonimidoyl]carbamate(110-1-1).

Step 2

A solution of TBAF (1.0 M, 19.7 mL, 19.7 mmol) was added to a solutionof 110-1-1 (6.64 g, 15.1 mmol) in anhydrous THF at 0° C. After 1 h at 0°C., the reaction was complete. The THF was removed under reducedpressure. The residue was diluted with water (80 mL) and EtOAc (80 mL).The phases were separated, and the aqueous phase was extracted withEtOAc (3×50 mL). The combined organic phases were washed with brine anddried over sodium sulfate. The solvent was removed pressure and theresidue was subjected to flash chromatography (0-65% EtOAc/hexanes 120 ggold isco column with solid loading). ELSD along with UV were used forpeak detection. The fractions containing product were combined and thesolvent was removed under reduced pressure, providing[(1S)-1-phenylethyl]N-[[(1R,2S)-1,2-dimethylpent-4-enyl]sulfonimidoyl]carbamate as a mixtureof diastereomers at sulfur. The solid was subjected to chiral SFCseparation, with methanol as a co-solvent using a ChiralPak IC column.

The first eluted diasteromer (110-1-2, RT=2.37 min on ChiralPak IC with15% methanol co-solvent, absolute stereochemistry tentatively assignedas drawn). 1H NMR (400 MHz, chloroform-d) δ 7.45-7.33 (m, 4H), 7.33-7.30(m, 1H), 5.73 (q, J=6.7 Hz, 1H), 5.48 (dddd, J=16.4, 10.1, 8.2, 6.0 Hz,1H), 5.06-4.93 (m, 2H), 3.41 (qd, J=7.0, 2.2 Hz, 1H), 2.53-2.39 (m, 1H),2.07 (dt, J=14.0, 6.2 Hz, 1H), 2.00-1.86 (m, 1H), 1.59 (d, J=6.7 Hz,3H), 1.34 (d, J=7.0 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H).

The second eluted diasteromer (110-1-3, Rt=3.92 min on ChiralPak IC with15% methanol co-solvent, absolute stereochemistry tentatively assignedas drawn). 1H NMR (400 MHz, chloroform-d) δ 7.43-7.32 (m, 4H), 7.33-7.29(m, 1H), 5.75 (q, J=6.6 Hz, 1H), 5.71-5.62 (m, 1H), 5.13-5.03 (m, 2H),3.38 (qd, J=7.1, 2.3 Hz, 1H), 2.47 (dtd, J=8.9, 6.9, 2.2 Hz, 1H), 2.11(dtt, J=13.1, 6.5, 1.4 Hz, 1H), 2.07-1.96 (m, 1H), 1.59 (d, J=6.7 Hz,3H), 1.31 (d, J=7.0 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H).

Example 110 was synthesized in the same manner as Example 109 (Method1-Steps 3-6) using intermediate 110-1-2 instead of intermediate 109-1-2.1H NMR (400 MHz, Chloroform-d) δ 7.778 (d, J=8.5 Hz, 1H), 7.45 (dd,J=8.3, 1.9 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.5, 2.3 Hz,1H), 7.10 (d, J=2.4 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 5.91 (dt, J=15.8,5.8 Hz, 1H), 5.69 (dd, J=15.8, 6.8 Hz, 1H), 4.18-3.95 (m, 2H), 3.87 (dd,J=14.9, 3.4 Hz, 1H), 3.73 (s, 5H), 3.41-3.23 (m, 4H), 3.01 (dd, J=15.0,10.9 Hz, 1H), 2.89-2.72 (m, 2H), 2.62 (s, 2H), 2.46 (s, 1H), 2.31-2.01(m, 3H), 1.99-1.64 (m, 6H), 1.46 (s, 3H), 1.11 (d, J=6.9 Hz, 3H).LCMS-ESI+ (m/z): calcd for H+C₃₃H₄₂ClN₃O₄S: 612.26; found: 612.06.

Method 2

Step 1

To an ice-cold solution of intermediate 110-1-3 (second elutingdiasteromer from Example 110-method 1-step 2, 3.6 g, 11.10 mmol) andtrifluoroacetic anhydride (3.5 g, 16.64 mmol) in anhydrousdichloromethane was added TEA (2.32 mL, 16.64 mmol) under argon, andthen the solution was stirred for 30 min. The reaction mixture wasconcentrated to yield intermediate 110-2-1.

Step 2

To a stirred mixture of dichloromethane/trifluoroacetic acid (3/1) (200mL) was added intermediate 110-2-1 (4.2 g, 9.98 mmol). The mixture wasstirred at room temperature overnight. The solvent was removed underreduced pressure. Then water was added, and the mixture was extractedwith dichloromethane. The organic phase was dried over anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.The residue thus obtained was purified by normal phase chromatography(SiO₂, 1:2 Hex:EtOAc) to yield intermediate 110-2-2. 1H NMR (400 MHz,Chloroform-d) δ 5.70 (dddd, J=17.0, 10.2, 8.3, 5.8 Hz, 1H), 5.58 (s,2H), 5.22-5.01 (m, 2H), 3.56 (qd, J=7.0, 2.2 Hz, 1H), 2.63-2.42 (m, 1H),2.19 (dtt, J=15.1, 6.0, 1.6 Hz, 1H), 2.05-1.91 (m, 1H), 1.43 (d, J=7.0Hz, 3H), 1.08 (d, J=6.8 Hz, 3H).

Step 3

To a stirred solution of intermediate 109-1-4 (4.0 g, 8.29 mmol) in DCMwas added EDCI (2.5 g, 16.6 mmol) and DMAP (2.0 g, 16.6 mmol). Thereaction mixture was stirred for 10 mins at room temperature.Intermediate 110-2-2 (2.4 g, 9.13 mmol) was added and the resultingsuspension was stirred overnight at room temperature. The reactionmixture was quenched with water and washed with DCM, aqueous NaHCO₃, 1 Naqueous HCl, and brine. The organic layer was dried with Mg₂SO₄ and thesolvent was removed under reduced pressure to afford the crude residue,which was subjected to column chromatography (SiO₂, 50-90% Hex/EtOAc) togive the desired intermediate 110-2-3.

Step 4

Intermediate 110-2-3 (1.2 g, 1.57 mmol), TFA (360 mg, 3.15 mmol) andHoveyda Grubbs generation 2 catalyst (196 mg, 0.32 mmol) were stirred in1,2-dichloroethane (150 mL) at 60° C. for 2 h. More catalyst was added(196 mg, 0.32 mmol) and the mixture stirred at 60° C. for 24 hr. Afterconcentration, the residue was purified by silica gel columnchromatography (5-95% Hex/EtOAc) to afford intermediate 110-2-4.

Step 5

To a stirred solution of intermediate 110-2-4 (200 mg, 0.28 mmol) inMeOH (10 ml) was added water (2 mL) and then K₂CO₃ (195 mg, 1.41 mmol).The reaction mixture was stirred at 60° C. for 24 hrs. Mixture wasevaporated under reduced pressure and then dissolved in DCM. Water wasadded, and then the mixture was extracted with DCM. Combined organiclayers was washed with brine, dried over Mg₂SO₄, filtered, concentrated,and purified by silica gel column chromatography (50-90% hexanes/EtOAc)to give Example 110.

Method 3 Step 1

To a solution of intermediate 1-5 (Example 1-step 5, 1 g, 3.44 mmol) inTHF (50 mL) at −50° C., was added n-butyl lithium (1.6 M in hexanes, 4.6mL, 7.40 mmol) was added dropwise over 5 min. The mixture was left tostir for 15 min. Concurrently (4-nitrophenyl) [(1S)-1-phenylethyl]carbonate (5-3-1, 1.3 g, 4.47 mmol) was azeotroped with toluene (3×20mL). The material was taken up in anhydrous tetrahydrofuran (30 mL)under an atmosphere of argon. The solution was added to the reaction viacannula over 5 min. The reaction was initially yellow but turned verydark (green). After 15 min the reaction was warmed to 0° C. (ice bath).The reaction turned yellow while warming. After 3 h, TLC (20%EtOAc/hexanes visualized with KMnO₄ stain) showed the reaction wascomplete. The reaction was quenched with water (75 mL) at 0° C. EtOAc(50 mL) was added. The phases were separated, and the aqueous phase wasextracted with EtOAc (2×50 mL). The combined organic phases were washedwith sat NaHCO₃ (75 mL) and brine (75 mL). The organic phase was driedover sodium sulfate and the solvent was removed under reduced pressure.The resulting crude product was redissolved in hexanes and purified byflash column chromatography (silica gel, 0 to 100% dichloromethane inhexanes, ELSD detector). ELSD-active fractions were assayed by silicagel TLC (3:1 hexanes:ethyl acetate, KMnO₄ stain); and the diastereomericproducts were co-eluted at 70-100% dichloromethane. The crude productmixture was redissolved in hexanes and again purified by flash columnchromatography (silica gel, 0 to 20% ethyl acetate in hexanes, ELSDdetector). ELSD-active fractions were assayed by silica gel TLC (3:1hexanes:ethyl acetate, KMnO₄ stain). The first-eluting peak eluted(110-3-1, absolute stereochemistry tentatively assigned as drawn) at 10%ethyl acetate, while the later eluting peak (110-3-2, absolutestereochemistry tentatively assigned as drawn) eluted at 15% ethylacetate,

Step 2

A solution of TBAF (1.0 M, 2.84 mL, 2.84 mmol) was added to a solutionof the intermediate 110-3-1 (830 mg, 1.89 mmol) in anhydrous THF at 0°C. After 60 min at 0° C., the reaction was complete. The solvent wasremoved under reduced pressure. The residue was diluted with water (80mL) and EtOAc (80 mL). The phases were separated, and the aqueous phasewas extracted with EtOAc (3×50 mL). The combined organic phases werewashed with brine, and dried over sodium sulfate. The solvent wasremoved pressure and the residue was subjected to flash chromatography(0-50% EtOAc/hexanes, 80 g silica gel). ELSD along with UV were used forpeak detection. The fractions containing product were combined and thesolvent was removed under reduced pressure, to give intermediate110-1-2.

Preparation of Example 110

Example 110 was synthesized in the same manner as Example 110 (Method 1)using intermediate 110-1-2.

Method 4

Step 1

Intermediate 110-1-3 was also prepared in similar manner to method3-step 2 (Example 110) using intermediate 110-3-2 instead ofintermediate 110-3-1.

Preparation of Example 110

Example 110 was synthesized in the same manner as Example 109 (Method 2)using intermediate 110-1-3.

Example 111

To the mixture of Example 109 (10 mg, 0.0167 mmol) in DCM (0.6 mL) wasadded ACN (1.7 mL) at rt. Then 4-dimethylaminopyridine (10.2 mg, 0.0836mmol) and diphenyl carbonate (28.6 mg, 0.134 mmol) were added to themixture and stirred at room temperature. After 5 hours,pyrimidin-2-amine (12.7 mg, 0.134 mmol) was added and the reaction washeated at 60° C. for 5 hours and then room temperature overnight. Thereaction was concentrated, redissolved in DMF (1.2 mL), filtered, andpurified by Gilson reverse phase prep HPLC, eluted with 60-100% ACN/H₂Owith 0.1% TFA. ¹H NMR (400 MHz, Methanol-d4) δ 8.73 (d, J=5.1 Hz, 2H),7.76 (d, J=8.5 Hz, 1H), 7.38-6.82 (m, 7H), 6.14 (dq, J=14.4, 6.6 Hz,1H), 5.62 (dd, J=15.4, 8.3 Hz, 1H), 4.21 (dd, J=14.8, 6.3 Hz, 1H),4.12-4.01 (m, 3H), 3.91-3.64 (m, 3H), 3.29 (s, 3H), 3.08 (dd, J=15.2,10.0 Hz, 1H), 2.89-2.71 (m, 2H), 2.60-2.37 (m, 3H), 2.32-2.06 (m, 3H),2.02-1.67 (m, 7H), 1.45 (t, J=11.1 Hz, 1H), 1.15 (dd, J=8.4, 6.3 Hz,3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₃ClN₆O₅S: 719.2; found:719.5.

Example 112

Example 112 was synthesized in the same manner as Example 111 using(3S)-tetrahydrofuran-3-amine hydrochloride instead of pyrimidin-2-amine,Hunig's base (8.64 mg, 0.0669 mmol) was also added to this reaction. 1HNMR (400 MHz, Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H), 7.24-7.10 (m, 3H),7.03-6.88 (m, 2H), 6.23-5.97 (m, 1H), 5.64-5.50 (m, 1H), 4.37-4.21 (m,2H), 4.11-4.01 (m, 2H), 3.98-3.75 (m, 6H), 3.72-3.48 (m, 3H), 3.28 (s,3H), 3.08 (dd, J=15.3, 10.2 Hz, 1H), 2.89-2.71 (m, 2H), 2.57-2.33 (m,3H), 2.31-2.09 (m, 3H), 1.98-1.73 (m, 8H), 1.44 (t, J=11.8 Hz, 1H), 1.14(d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₇ClN₄O₆S:711.3; found: 710.8.

Example 113

To the mixture of 1-methylpyrazole-4-carboxylic acid (3.76 mg, 0.0298mmol) in DCM (1.0 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (5.71 mg, 0.0298 mmol)and 4-dimethylaminopyridine (3.64 mg, 0.0298 mmol). The mixture wasstirred at rt for 5 minutes, then Example 5 (8.7 mg, 0.0149 mmol) wasadded, and the reaction was stirred at room temperature overnight. Thereaction mixture was then concentrated, redissolved in DMF (1.2 mL),filtered, and purified by Gilson reverse phase prep HPLC, eluted with60-100% ACN/H₂O with 0.1% TFA to give Example 113. ¹H NMR (400 MHz,Methanol-d4) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.36(d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.07 (d, J=2.1 Hz, 1H), 6.99-6.83 (m,2H), 5.98-5.90 (m, 1H), 5.86 (dd, J=16.0, 8.2 Hz, 1H), 3.97 (d, J=29.0Hz, 6H), 3.77 (d, J=15.0 Hz, 1H), 3.71-3.65 (m, 2H), 3.62-3.55 (m, 2H),3.47 (d, J=14.3 Hz, 1H), 3.37 (s, 3H), 3.16 (d, J=26.2 Hz, 1H),2.88-2.74 (m, 3H), 2.50 (s, 2H), 2.30 (d, J=9.2 Hz, 2H), 2.10 (d, J=14.0Hz, 3H), 2.00-1.84 (m, 4H), 1.41 (d, J=11.9 Hz, 1H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₆H₄₂ClN₅O₅S: 692.2; found: 691.973.

Example 114

Example 114 was synthesized in the same manner as Example 75 usingExample 109 and methyl 3-aminoazetidine-1-carboxylate. ¹H NMR (400 MHz,methanol-d₄) δ 7.72 (d, J=8.5 Hz, 1H), 7.17-7.12 (m, 2H), 7.09 (d, J=2.3Hz, 1H), 6.94 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.07-5.89 (m, 1H), 5.57(dd, J=15.3, 9.0 Hz, 1H), 4.60-4.41 (m, 1H), 4.25 (t, J=8.5 Hz, 3H),4.13-3.98 (m, 2H), 3.96-3.79 (m, 3H), 3.75 (dd, J=9.0, 3.7 Hz, 1H),3.69-3.62 (m, 1H), 3.66 (s, 3H), 3.29-3.23 (m, 1H), 3.25 (s, 3H), 3.06(dd, J=15.3, 10.3 Hz, 1H), 2.88-2.66 (m, 2H), 2.53-2.28 (m, 3H),2.24-2.05 (m, 3H), 2.00-1.65 (m, 7H), 1.42 (t, J=12.4 Hz, 1H), 1.12 (d,J=6.5 Hz, 3H). LCMS-ESI+: calc'd for C₃₈H₄₈ClN₅O₇S: 754.29 (M+H); found:753.97 (M+H).

Example 115

Example 115 was synthesized in the same manner as Example 75 usingExample 109 and (1S,2R)-2-fluorocyclopropanamine. ¹H NMR (400 MHz,Methanol-d₄) δ 7.75 (d, J=8.5 Hz, 1H), 7.24-7.15 (m, 2H), 7.12 (d, J=2.3Hz, 1H), 7.03-6.97 (m, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.03 (dd, J=15.0,7.6 Hz, 1H), 5.59 (dd, J=15.2, 8.9 Hz, 1H), 4.79-4.54 (m, 1H), 4.29 (dd,J=14.9, 6.4 Hz, 1H), 4.14-4.01 (m, 2H), 3.91-3.73 (m, 3H), 3.68 (d,J=14.5 Hz, 1H), 3.31-3.24 (m, 1H), 3.27 (s, 3H), 3.07 (dd, J=15.2, 10.3Hz, 1H), 2.89-2.72 (m, 2H), 2.68 (dt, J=10.2, 5.5 Hz, 1H), 2.57-2.31 (m,3H), 2.28-2.07 (m, 3H), 2.03-1.65 (m, 6H), 1.44 (t, J=12.5 Hz, 1H),1.24-1.07 (m, 4H), 1.01-0.84 (m, 1H). LCMS-ESI+: calc'd forC₃₆H₄₄ClFN₄O₅S: 699.27 (M+H); found: 698.73 (M+H).

Example 116

Example 116 was synthesized in the same manner as Example 75 usingExample 109 and (1R,2S)-2-fluorocyclopropanamine. ¹H NMR (400 MHz,Methanol-d₄) δ 7.75 (d, J=8.5 Hz, 1H), 7.24-7.15 (m, 2H), 7.12 (d, J=2.3Hz, 1H), 7.00 (s, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.11-5.97 (m, 1H), 5.58(dd, J=15.3, 8.9 Hz, 1H), 4.66 (dtd, J=64.4, 5.7, 3.2 Hz, 1H), 4.30 (dd,J=14.9, 6.3 Hz, 1H), 4.15-3.99 (m, 2H), 3.86 (d, J=14.8 Hz, 2H), 3.78(dd, J=9.0, 3.7 Hz, 1H), 3.68 (d, J=14.6 Hz, 1H), 3.31-3.28 (m, 1H),3.27 (s, 3H), 3.07 (dd, J=15.2, 10.3 Hz, 1H), 2.89-2.71 (m, 2H), 2.67(dt, J=9.4, 5.3 Hz, 1H), 2.55-2.30 (m, 3H), 2.26-2.08 (m, 3H), 2.01-1.67(m, 6H), 1.44 (t, J=12.2 Hz, 1H), 1.21-1.06 (m, 4H), 1.02-0.87 (m, 1H).LCMS-ESI+: calc'd for C₃₆H₄₄ClFN₄O₅S: 699.27 (M+H); found: 698.65 (M+H).

Example 117

Example 117 was prepared in a similar manner to Example 75 using (1S,2R)-2-methylcyclopropan-1-amine hydrochloride, triethylamine and Example109. 1H NMR (400 MHz, methanol-d4) δ 7.76 (d, J=8.5 Hz, 2H), 7.38 (s,2H), 7.18 (d, J=9.3 Hz, 2H), 7.12 (s, 2H), 6.85 (s, 2H), 6.24 (s, 2H),5.59 (s, 2H), 4.60 (s, 1H), 4.11-3.97 (m, 4H), 3.83-3.66 (m, 9H), 2.80(d, J=19.4 Hz, 4H), 2.63 (s, 3H), 2.32 (s, 4H), 2.20-2.03 (m, 5H), 1.96(s, 6H), 1.77 (s, 6H), 1.46 (s, 3H), 1.31 (s, 1H), 1.07 (d, J=6.1 Hz,23H), 0.83 (ddt, J=12.2, 6.1, 3.0 Hz, 3H), 0.61 (ddd, J=9.0, 5.1, 3.6Hz, 4H), 0.51-0.39 (m, 6H). LCMS-ESI+ (m/z): [M+H] Calculated forC₃₇H₄₇ClN₄O₅S: 695.32; found 694.99.

Example 118

Synthesis of 5-chloro-1-methyl-1H-pyrrole-3-carboxylic acid: To asolution of 5-chloro-1H-pyrrole-3-carboxylic acid (0.075 g; 0.515 mmol)in 1.0 mL DMSO was added freshly ground potassium hydroxide (KOH(solid); 0.231 g; 4.12 mmol). The heterogeneous slurry was stirred for50 minutes before addition of iodomethane (Mel; 0.048 mL; 0.109 g; 0.773mmol). The mixture was allowed to stir at ambient temperature for 4hours before diluting the reaction mixture with 10 mL of each CH₂Cl₂ and1 N HCl (aq.) The biphasic mixture was stirred for at least ten minutesbefore layers were separated. The aqueous layer was back extracted with10 mL of each isopropyl acetate and ethyl acetate. The combined organicphases were washed with 10 mL H₂O and dried over anhydrous Na₂SO₄. Theorganic phases were concentrated to dryness in vacuo and used directlyin the next step (vida infra) (62 mg; 82.7% yield) (¹H NMR (400 MHz,DMSO-d₆) δ 11.98 (s, 1H), 7.47 (d, J=2.1 Hz, 1H), 6.39 (d, J=2.1 Hz,1H), 3.60 (s, 3H), 2.55 (s, 1H). LCMS-ESI+ (m/z): [M+H] calculated forC₆H₆ClNO₂: 160.01; found 160.07.

Example 118 was prepared in a similar manner to Example 106 using5-chloro-1-methyl-1H-pyrrole-3-carboxylic acid and Example 109. 1H NMR(400 MHz, methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H), 7.38-7.27 (m, 2H), 7.15(dd, J=8.5, 2.4 Hz, 1H), 7.11-7.01 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 6.48(s, 1H), 6.17 (dd, J=14.8, 7.4 Hz, 1H), 5.51 (dd, J=15.4, 8.7 Hz, 1H),4.15 (s, 1H), 4.10 (d, J=7.1 Hz, 0H), 4.09-3.95 (m, 2H), 3.86-3.70 (m,2H), 3.60 (s, 4H), 3.25 (s, 4H), 3.03 (dd, J=15.0, 9.8 Hz, 1H),2.86-2.67 (m, 2H), 2.59 (d, J=10.4 Hz, 1H), 2.41 (s, 3H), 2.22-2.05 (m,4H), 1.99 (d, J=9.6 Hz, 2H), 1.91 (d, J=7.5 Hz, 2H), 1.79 (dd, J=19.5,8.7 Hz, 1H), 1.73 (s, 2H), 1.69 (d, J=8.8 Hz, 0H), 1.41 (t, J=12.7 Hz,1H), 1.33-1.19 (m, 2H), 1.06 (d, J=6.5 Hz, 3H), 0.89 (dd, J=7.3, 3.8 Hz,1H). LCMS-ESI+ (m/z): [M+H] calculated for C₃₈H₄₄Cl₂N₄O₅S: 739.24;found: 739.75 (M+H).

Example 119

Example 119 was prepared in a similar manner to Example 18 using1-(difluoromethyl)-1H-pyrazole-4-carboxylic acid and Example 109. ¹H NMR(400 MHz, Methanol-d₄) δ 8.48 (s, 1H), 8.09 (s, 1H), 7.77 (d, J=8.5 Hz,1H), 7.66 (s, 0H), 7.52 (s, 1H), 7.40-7.32 (m, 1H), 7.18 (dd, J=8.5, 2.4Hz, 1H), 7.10 (dd, J=6.4, 2.1 Hz, 2H), 6.84 (d, J=8.2 Hz, 1H), 6.22 (dt,J=14.4, 6.9 Hz, 1H), 5.56 (dd, J=15.4, 8.6 Hz, 1H), 4.22-3.98 (m, 3H),3.87-3.74 (m, 2H), 3.78-3.61 (m, 4H), 3.55 (dt, J=11.6, 2.8 Hz, 0H),3.35 (s, 0H), 3.28 (s, 3H), 3.06 (dd, J=15.2, 10.2 Hz, 1H), 2.88-2.70(m, 2H), 2.70-2.61 (m, 1H), 2.52-2.38 (m, 1H), 2.29 (s, 1H), 2.21 (dt,J=14.1, 7.0 Hz, 1H), 2.12 (d, J=13.7 Hz, 1H), 1.94 (d, J=7.0 Hz, 3H),1.88-1.69 (m, 2H), 1.44 (t, J=11.9 Hz, 1H), 1.31 (s, 0H), 1.11 (d, J=6.8Hz, 3H). ¹⁹F NMR (376 MHz, methanol-d₄) δ −97.35. LCMS-ESI+ (m/z): [M+H]calculated for C₃₇H₄₂ClF₂N₅O₅S: 742.26; found 742.13.

Example 120

Example 118 was prepared in a similar manner to Example 18, using1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid and Example 109. ¹H NMR(400 MHz, methanol-d₄) δ 8.11 (s, 1H), 7.92 (s, 1H), 7.77 (d, J=8.6 Hz,1H), 7.41-7.24 (m, 3H), 7.18 (dd, J=8.4, 2.3 Hz, 1H), 7.13-7.06 (m, 2H),6.83 (d, J=8.2 Hz, 1H), 6.22 (dt, J=14.4, 6.8 Hz, 1H), 5.75-5.67 (m,0H), 5.55 (dd, J=15.4, 8.7 Hz, 1H), 5.07 (s, 0H), 4.31 (t, J=5.1 Hz,2H), 4.22-3.97 (m, 3H), 3.84 (d, J=14.8 Hz, 1H), 3.82-3.63 (m, 7H),3.61-3.51 (m, 0H), 3.29 (d, J=12.4 Hz, 5H), 3.06 (dd, J=15.0, 10.0 Hz,1H), 2.88-2.74 (m, 2H), 2.64 (d, J=13.8 Hz, 1H), 2.43 (s, 2H), 2.27 (s,1H), 2.23-2.08 (m, 3H), 1.94 (d, J=6.3 Hz, 3H), 1.88-1.68 (m, 2H), 1.52(d, J=6.6 Hz, 1H), 1.50-1.38 (m, 1H), 1.31 (s, 3H), 1.10 (dd, J=6.7, 3.6Hz, 4H), 0.93 (d, J=5.7 Hz, 0H), 0.90 (s, 2H), 0.12 (s, 1H). LCMS-ESI+(m/z): [M+H] calculated for C₃₉H₄₈ClN₅O₆S: 750.30; found 750.08.

Example 121

Example 121 was synthesized in the same manner as Example 18 using(S)-2-hydroxy-3-phenylpropionic acid and Example 109. 1H NMR (400 MHz,Acetonitrile-d3) δ 7.72 (d, J=8.5 Hz, 1H), 7.36-7.21 (m, 6H), 7.19 (dd,J=8.6, 2.4 Hz, 1H), 7.16-7.10 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.01 (dt,J=14.0, 6.5 Hz, 1H), 5.57 (dd, J=15.5, 7.9 Hz, 1H), 4.43 (dd, J=8.1, 4.2Hz, 1H), 4.06 (d, J=12.1 Hz, 1H), 4.00 (d, J=12.1 Hz, 1H), 3.86 (s, 1H),3.80 (d, J=15.3 Hz, 1H), 3.74-3.66 (m, 2H), 3.34 (d, J=14.3 Hz, 1H),3.20 (s, 3H), 3.17 (dd, J=14.1, 4.2 Hz, 1H), 3.05 (dd, J=15.2, 10.1 Hz,1H), 2.94 (dd, J=14.0, 8.2 Hz, 1H), 2.86-2.68 (m, 2H), 2.52-2.34 (m,3H), 2.14 (t, J=8.5 Hz, 2H), 2.10-2.00 (m, 1H), 1.90-1.59 (m, 9H), 1.41(dt, J=14.6, 7.8 Hz, 1H), 1.05 (d, J=6.3 Hz, 3H). ¹⁹F NMR (376 MHz,acetonitrile-d3) 5-77.38. LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₁H₄₈ClN₃O₆S: 746.3; found: 746.0.

Example 122

Example 122 was synthesized in the same manner as Example 18 using(R)-2-hydroxy-3-phenylpropionic acid and Example 109. 1H NMR (400 MHz,Acetonitrile-d3) δ 7.73 (d, J=8.5 Hz, 1H), 7.36-7.27 (m, 4H), 7.28-7.22(m, 1H), 7.20 (dd, J=8.5, 2.4 Hz, 1H), 7.14 (dd, J=9.3, 2.2 Hz, 2H),6.88 (d, J=8.3 Hz, 1H), 6.00 (dt, J=14.6, 6.9 Hz, 1H), 5.55 (dd, J=15.6,7.9 Hz, 1H), 4.49 (dd, J=7.6, 4.1 Hz, 1H), 4.06 (d, J=12.1 Hz, 1H), 4.00(d, J=12.1 Hz, 1H), 3.83-3.75 (m, 2H), 3.75-3.64 (m, 2H), 3.34 (d,J=14.3 Hz, 1H), 3.20 (s, 3H), 3.15 (dd, J=14.1, 4.1 Hz, 1H), 3.04 (dd,J=15.1, 10.3 Hz, 1H), 2.96 (dd, J=14.1, 7.6 Hz, 1H), 2.86-2.64 (m, 2H),2.49-2.32 (m, 3H), 2.11-1.99 (m, 2H), 1.92-1.57 (m, 10H), 1.40 (dt,J=15.1, 8.0 Hz, 1H), 0.99 (d, J=6.9 Hz, 3H). 19F NMR (376 MHz,Acetonitrile-d3) 5-77.38. LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₁H₄₈ClN₃O₆S: 746.3; found: 746.0.

Example 123

Example 123 was synthesized in the same manner as Example 18 using1-cyclopropyl-1H-pyrazole-4-carboxylic acid and Example 109. ¹H NMR (400MHz, Acetonitrile-d3) δ 8.29 (s, 1H), 7.90 (d, J=0.6 Hz, 1H), 7.60 (d,J=8.5 Hz, 1H), 7.23 (dd, J=8.2, 1.9 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H),7.04-6.92 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 6.01 (dt, J=13.7, 6.6 Hz,1H), 5.60 (dd, J=15.4, 8.4 Hz, 1H), 4.54 (hept, J=6.6 Hz, 1H), 4.12 (dd,J=14.8, 6.3 Hz, 1H), 3.97 (s, 2H), 3.86-3.67 (m, 3H), 3.63 (d, J=14.4Hz, 1H), 3.35 (d, J=14.4 Hz, 1H), 3.21 (s, 3H), 3.06 (dd, J=15.2, 10.2Hz, 1H), 2.86-2.65 (m, 2H), 2.59 (d, J=13.3 Hz, 1H), 2.47-2.32 (m, 2H),2.19 (dq, J=14.5, 7.2 Hz, 2H), 2.08-1.97 (m, 2H), 1.90 (d, J=4.0 Hz,2H), 1.83-1.63 (m, 3H), 1.46 (t, J=6.8 Hz, 6H), 1.34 (dt, J=13.3, 8.0Hz, 1H), 1.08 (d, J=6.4 Hz, 3H). ¹⁹F NMR (376 MHz, Acetonitrile-d3)5-77.37. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₈ClN₅O₅S: 734.3; found:733.8.

Example 124

Example 124 was synthesized in the same manner as Example 18 using2-((4-methyltetrahydro-2H-pyran-4-yl)oxy)acetic acid and Example 109. ¹HNMR (400 MHz, Acetonitrile-d3) δ 7.72 (d, J=8.5 Hz, 1H), 7.34 (dd,J=8.2, 1.9 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz,1H), 7.13 (d, J=2.3 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.04 (dt, J=14.7,6.7 Hz, 1H), 5.58 (ddd, J=15.5, 7.5, 1.4 Hz, 1H), 4.08 (d, J=1.0 Hz,2H), 4.05 (d, J=12.1 Hz, 1H), 3.99 (d, J=12.1 Hz, 1H), 3.90 (dd, J=15.0,5.3 Hz, 1H), 3.81 (d, J=7.1 Hz, 1H), 3.79-3.75 (m, 1H), 3.75-3.66 (m,3H), 3.61 (dt, J=11.6, 4.2 Hz, 2H), 3.36 (d, J=14.5 Hz, 1H), 3.21 (s,3H), 3.05 (dd, J=15.1, 10.8 Hz, 1H), 2.85-2.66 (m, 2H), 2.57-2.45 (m,2H), 2.45-2.34 (m, 1H), 2.33-2.21 (m, 1H), 2.15 (dt, J=14.7, 7.4 Hz,1H), 2.09-1.99 (m, 1H), 1.92-1.85 (m, 3H), 1.84-1.56 (m, 8H), 1.40 (dt,J=14.9, 7.6 Hz, 1H), 1.25 (s, 3H), 1.07 (d, J=6.9 Hz, 3H). ¹⁹F NMR (376MHz, acetonitrile-d3) 5-77.38. LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₀H₅₂ClN₃O₇S: 754.3; found: 753.9.

Example 125

Example 125 was synthesized in the same manner as Example 18 using6-oxaspiro[3.4]octane-2-carboxylic acid and Example 109. ¹H NMR (400MHz, Acetonitrile-d₃) δ 7.59 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.2, 1.9 Hz,1H), 7.09 (d, J=2.3 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.94 (dd, J=8.6,2.3 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.15-5.99 (m, 1H), 5.64 (dd,J=15.5, 8.2 Hz, 1H), 4.01-3.90 (m, 3H), 3.85 (ddd, J=14.7, 4.9, 3.1 Hz,1H), 3.79-3.64 (m, 6H), 3.61 (d, J=5.6 Hz, 2H), 3.45-3.29 (m, 2H), 3.26(s, 4H), 3.07 (dd, J=15.2, 10.1 Hz, 1H), 2.75 (dtt, J=43.7, 17.9, 8.8Hz, 4H), 2.51-2.13 (m, 7H), 2.10-1.99 (m, 3H), 1.95-1.89 (m, 2H),1.88-1.63 (m, 2H), 1.43-1.23 (m, 2H), 1.10 (dd, J=6.8, 1.1 Hz, 3H).LCMS-ESI+(m/z): calcd for H+C₄₀H₅₀ClN₃O₆S: 736.3; found: 736.12.

Example 126

Example 126 was synthesized in the same manner as Example 18 using3-chloro-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. ¹H NMR(400 MHz, methanol-d₄) δ 8.23 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.18 (dd,J=8.1, 1.9 Hz, 1H), 7.13 (s, 1H), 7.11 (s, 2H), 7.00-6.87 (m, 2H), 6.04(dd, J=15.0, 7.3 Hz, 1H), 5.62 (dd, J=15.2, 8.9 Hz, 1H), 4.37 (dd,J=14.8, 6.4 Hz, 1H), 4.07 (s, 2H), 3.89 (s, 3H), 3.88-3.75 (m, 3H), 3.67(d, J=14.2 Hz, 1H), 3.28 (s, 3H), 3.19-3.00 (m, 1H), 2.91-2.70 (m, 2H),2.62-2.45 (m, 1H), 2.44-2.07 (m, 4H), 2.05-1.73 (m, 3H), 1.44 (t, J=12.7Hz, 1H), 1.31 (s, 1H), 1.17 (d, J=6.3 Hz, 3H). LCMS-ESI+ (m/z): calcdfor C₃₇H₄₃C₁₂N₅O₅S: 739.24; found: 739.99.

Example 127

Example 127 was synthesized in the same manner as Example 18 usingcis-3-methoxycyclobutanecarboxylic acid and Example 109. ¹H NMR (400MHz, methanol-d₄) δ 7.75 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.2, 1.9 Hz,1H), 7.17 (dd, J=8.5, 2.4 Hz, 1H), 7.10 (dd, J=9.1, 2.1 Hz, 2H), 6.88(d, J=8.2 Hz, 1H), 6.13 (dt, J=14.4, 6.9 Hz, 1H), 5.61 (dd, J=15.4, 8.5Hz, 1H), 4.17 (dd, J=14.8, 6.7 Hz, 1H), 4.11-4.00 (m, 2H), 3.96 (dd,J=14.8, 5.3 Hz, 1H), 3.91-3.80 (m, 2H), 3.76 (d, J=8.6 Hz, 1H), 3.68 (d,J=14.2 Hz, 1H), 3.27 (d, J=13.7 Hz, 7H), 3.06 (dd, J=15.1, 9.8 Hz, 1H),2.88-2.70 (m, 3H), 2.58-2.47 (m, 3H), 2.45 (s, 2H), 2.34-2.19 (m, 2H),2.14 (dd, J=19.5, 10.9 Hz, 3H), 1.95 (s, 3H), 1.90-1.70 (m, 3H), 1.44(t, J=12.4 Hz, 1H), 1.13 (d, J=6.8 Hz, 3H). LCMS-ESI+: calc'd forC₃₈H₄₈ClN₃O₆S: 710.3 (M+H); found: 710.1 (M+H).

Example 128

Example 128 was synthesized in the same manner as Example 18 usingtrans-3-methoxycyclobutanecarboxylic acid and Example 109. ¹H NMR (400MHz, methanol-d₄) δ 7.76 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.1, 1.9 Hz,1H), 7.18 (dd, J=8.5, 2.4 Hz, 1H), 7.11 (dd, J=4.1, 2.2 Hz, 2H), 6.88(d, J=8.2 Hz, 1H), 6.14 (dt, J=14.5, 6.9 Hz, 1H), 5.62 (dd, J=15.4, 8.4Hz, 1H), 4.20-4.08 (m, 2H), 4.06 (dd, J=7.6, 3.7 Hz, 2H), 4.03-3.93 (m,2H), 3.85 (d, J=15.0 Hz, 1H), 3.77 (dd, J=8.5, 2.8 Hz, 1H), 3.69 (d,J=14.2 Hz, 1H), 3.36 (s, 1H), 3.30 (s, 3H), 3.26 (s, 3H), 3.21-3.12 (m,1H), 3.07 (dd, J=15.2, 9.8 Hz, 1H), 2.89-2.70 (m, 2H), 2.57 (qd, J=8.1,4.1 Hz, 2H), 2.46 (s, 2H), 2.36-2.17 (m, 3H), 2.12 (d, J=13.9 Hz, 2H),2.02-1.67 (m, 6H), 1.45 (t, J=12.5 Hz, 1H), 1.14 (d, J=6.9 Hz, 3H).LCMS-ESI+: calc'd for C₃₈H₄₈ClN₃O₆S: 710.3 (M+H); found: 710.1 (M+H).

Example 129

Example 129 was synthesized in the same manner as Example 75 usingExample 109 andtrans-rac-(1R,2S)-2-(1-methylpyrazol-4-yl)cyclopropanamine hydrogenchloride and triethylamine. ¹H NMR (400 MHz, methanol-d₄) δ 7.67 (d,J=8.6 Hz, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.09(s, 1H), 6.98 (s, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.10-6.01 (m, 1H),5.70-5.59 (m, 1H), 4.23 (dd, J=14.8, 6.8 Hz, 1H), 4.02 (s, 2H), 3.83 (s,5H), 3.65 (d, J=14.2 Hz, 1H), 3.37 (s, 1H), 3.30 (s, 4H), 3.08 (dd,J=15.2, 9.9 Hz, 1H), 2.92-2.51 (m, 5H), 2.45 (s, 2H), 2.23 (s, 2H), 2.08(t, J=11.5 Hz, 2H), 2.02-1.85 (m, 4H), 1.81 (d, J=7.5 Hz, 2H), 1.40 (t,J=12.9 Hz, 1H), 1.19-1.12 (m, 3H), 1.03 (q, J=6.3 Hz, 1H). LCMS-ESI+:calc'd for C₄₀H₄₉ClN₆O₅S: 761.3 (M+H); found: 760.8 (M+H).

Example 130

Example 130 was synthesized in the same manner as Example 18 using1-ethylpyrrole-3-carboxylic acid and Example 109. 1H NMR (400 MHz,methanol-d4) δ 7.74 (d, J=8.4 Hz, 1H), 7.62 (t, J=1.9 Hz, 1H), 7.33 (d,J=8.5 Hz, 1H), 7.18-7.08 (m, 3H), 6.90 (d, J=8.2 Hz, 1H), 6.81 (dd,J=3.0, 2.1 Hz, 1H), 6.64 (dd, J=2.9, 1.8 Hz, 1H), 6.12 (dt, J=14.4, 6.6Hz, 1H), 5.62 (dd, J=15.4, 8.5 Hz, 1H), 4.24 (dd, J=14.6, 6.3 Hz, 1H),4.12-3.98 (m, 4H), 3.86 (d, J=15.0 Hz, 1H), 3.82-3.75 (m, 1H), 3.69 (d,J=14.3 Hz, 1H), 3.38 (s, 1H), 3.29 (s, 3H), 3.08 (dd, J=15.1, 10.0 Hz,1H), 2.89-2.70 (m, 2H), 2.57 (dd, J=12.9, 6.5 Hz, 1H), 2.46 (s, 2H),2.32-2.15 (m, 2H), 2.12 (d, J=13.7 Hz, 1H), 1.96 (d, J=6.2 Hz, 3H),1.88-1.69 (m, 3H), 1.46 (t, J=7.3 Hz, 4H), 1.31 (s, 1H), 1.14 (d, J=6.5Hz, 3H). LCMS-ESI+: calc'd for C₃₉H₄₇ClN₄O₅S: 719.3 (M+H); found: 718.8(M+H).

Example 131

Example 131 was synthesized in the same manner as Example 75 usingExample 109 and 1-(methoxymethyl)cyclopropanamine. 1H NMR (400 MHz,methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.25-7.14 (m, 2H), 7.11 (d, J=2.3Hz, 1H), 7.01 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.03 (dd, J=14.7, 7.4 Hz,1H), 5.59 (dd, J=15.3, 8.9 Hz, 1H), 4.31-4.22 (m, 1H), 4.13-4.00 (m,2H), 3.90-3.73 (m, 3H), 3.68 (d, J=14.2 Hz, 1H), 3.46 (d, J=8.2 Hz, 1H),3.39 (s, 3H), 3.27 (s, 4H), 3.07 (dd, J=15.3, 10.2 Hz, 1H), 2.92-2.70(m, 3H), 2.48 (d, J=7.6 Hz, 2H), 2.39 (d, J=9.2 Hz, 1H), 2.19 (dt,J=14.1, 7.0 Hz, 1H), 2.12 (d, J=13.1 Hz, 2H), 2.01-1.87 (m, 3H), 1.77(tq, J=17.6, 9.3, 8.8 Hz, 3H), 1.44 (t, J=11.6 Hz, 1H), 1.14 (d, J=6.6Hz, 3H), 0.83 (d, J=12.6 Hz, 3H). LCMS-ESI+: calc'd for C₃₈H₄₉ClN₄O₆S:725.3 (M+H); found: 724.8 (M+H).

Example 132

Example 132 was synthesized in the same manner as Example 75 usingExample 109 and 2-methoxyethan-1-amine. 1H NMR (400 MHz, methanol-d4) δ7.75 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.18 (dd, J=8.5, 2.4 Hz,1H), 7.11 (d, J=2.3 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.06(dd, J=15.0, 6.9 Hz, 1H), 5.58 (dd, J=15.3, 8.9 Hz, 1H), 4.27 (dd,J=14.7, 6.5 Hz, 1H), 4.14-3.96 (m, 2H), 3.91-3.62 (m, 4H), 3.49 (d,J=5.3 Hz, 2H), 3.38 (s, 3H), 3.27 (s, 3H), 3.07 (dd, J=15.2, 10.2 Hz,1H), 2.91-2.66 (m, 3H), 2.57-2.28 (m, 3H), 2.28-2.04 (m, 3H), 2.02-1.87(m, 3H), 1.87-1.66 (m, 3H), 1.54-1.36 (m, 2H), 1.31 (s, 1H), 1.13 (d,J=6.6 Hz, 3H). LCMS-ESI+: calc'd for C₃₆H₄₇ClN₄O₆S: 699.3 (M+H); found:698.6 (M+H).

Example 133

Example 133 was synthesized in the same manner as Example 18 using2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)acetic acid and Example110. 1H NMR (400 MHz, methanol-d4) δ 7.73 (d, J=8.8 Hz, 1H), 7.37 (dd,J=8.2, 1.8 Hz, 1H), 7.17 (dd, J=8.4, 2.4 Hz, 1H), 7.11 (d, J=2.0 Hz,1H), 7.08 (d, J=2.0 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 6.12-6.05 (m, 1H),5.56 (dd, J=15.2, 8.8 Hz, 1H), 4.18-4.11 (m, 2H), 4.08-3.83 (m, 4H),3.81-3.72 (m, 2H), 3.68 (s, 2H), 3.61 (d, J=14.4 Hz, 1H), 3.55-3.40 (m,3H), 3.37-3.31 (m, 2H), 3.26 (s, 3H), 3.16-3.08 (m, 1H), 2.88-2.69 (m,3H), 2.51-1.61 (m, 12H), 1.54-1.46 (m, 1H), 1.43 (d, J=6.8 Hz, 3H), 1.13(d, J=6.8 Hz, 3H). LCMS-ESI+: calc'd for C₄₀H₅₁ClFN₃O₇S: 772.3 (M+H);found: 772.2 (M+H).

Example 134

Example 134 was synthesized in the same manner as Example 18 using1-ethyl-1H-pyrazole-4-carboxylic acid and Example 109. 1H NMR (400 MHz,methanol-d4) δ 8.29 (s, 1H), 7.96 (s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.23(dd, J=8.2, 1.8 Hz, 1H), 7.14-7.07 (m, 2H), 6.99 (d, J=1.9 Hz, 1H), 6.91(d, J=8.2 Hz, 1H), 6.07 (dt, J=14.3, 6.7 Hz, 1H), 5.62 (dd, J=15.3, 8.8Hz, 1H), 4.34 (dd, J=14.8, 6.5 Hz, 1H), 4.24 (q, J=7.3 Hz, 2H), 4.06 (d,J=1.5 Hz, 2H), 3.92 (dd, J=14.7, 5.2 Hz, 1H), 3.84 (d, J=15.1 Hz, 1H),3.78 (dd, J=8.8, 3.3 Hz, 1H), 3.67 (d, J=14.3 Hz, 1H), 3.36 (d, J=2.5Hz, 1H), 3.29 (s, 3H), 3.09 (dd, J=15.2, 9.9 Hz, 1H), 2.93-2.65 (m, 3H),2.56 (d, J=10.0 Hz, 1H), 2.43 (dd, J=17.5, 8.9 Hz, 2H), 2.25 (dt,J=26.4, 9.7 Hz, 2H), 2.11 (d, J=13.5 Hz, 1H), 1.98 (dd, J=16.3, 5.2 Hz,2H), 1.82 (dt, J=23.0, 9.3 Hz, 4H), 1.50 (t, J=7.3 Hz, 3H), 1.16 (d,J=6.6 Hz, 3H). LCMS-ESI+: calc'd for C₃₈H₄₆ClN₅O₅S: 720.3 (M+H); found:719.0 (M+H).

Example 135

Step 1: Preparation of methyl 3-(2-formyl-1H-pyrrol-1-yl)propanoate

A solution of pyrrolcarboxaldehyde (5.0 g, 0.053 mol) in dry DMF (10 mL)was added dropwise, under nitrogen atmosphere, to a stirred suspensionof 60% sodium hydride (oil dispersion) (2.56 g, 0.063 mol) in dry DMF(40 mL). The temperature of the mixture was maintained at 0° C. Afteraddition was completed, stirring was continued at the same temperaturefor 30 min. Then a solution of methyl 3-bromopropanoate (13.17 g, 0.079mol) was added dropwise and the temperature was allowed to rise to roomtemperature. The reaction mixture was stirred at this temperature for 48h. Then water was added and the mixture was extracted withdichloromethane. The organic phase was dried over anhydrous magnesiumsulfate and the solvent removed under reduced pressure and purified bynormal phase chromatography (silica gel column, 0-80% EtOAc/Hexanes) togive methyl 3-(2-formyl-1H-pyrrol-1-yl)propanoate.

Step 2: Preparation of methyl 3H-pyrrolizine-6-carboxylate

A solution of methyl 3-(2-formyl-1H-pyrrol-1-yl)propanoate (2.0 g, 11.04mmol) in MeOH (20 mL) was added NaOMe (2.62 g, 12.14 mmol). The reactionmixture was stirred at 45° C. for 48 h. Then water was added and themixture was extracted with dichloromethane. The organic phase was driedover anhydrous magnesium sulfate and the solvent was removed underreduced pressure and purified by normal phase chromatography (silica gelcolumn, 0-80% EtOAc/hexanes) to give intermediate methyl3H-pyrrolizine-6-carboxylate. ¹H NMR (400 MHz, chloroform-d) δ 7.58 (p,J=1.2 Hz, 1H), 6.60 (dtd, J=6.1, 2.2, 0.7 Hz, 1H), 6.36 (q, J=0.9 Hz,1H), 6.31-6.21 (m, 1H), 4.50 (tt, J=2.2, 1.0 Hz, 2H), 3.83 (s, 3H).

Step 3: Preparation of 3H-pyrrolizine-6-carboxylic Acid

To a stirred solution of methyl 3H-pyrrolizine-6-carboxylate (0.3 g, 1.8mmol) in methanol (6 mL) was added 2N of LiOH (1 mL), and the reactionmixture was stirred at rt for 3 h. To the reaction mixture was added 2NHCl (1 mL) and concentrated. Water was added and the mixture wasextracted with dichloromethane. The organic phase was dried overanhydrous magnesium sulfate and the solvent was removed under reducedpressure to give 3H-pyrrolizine-6-carboxylic acid.

Step 4

Example 135 was synthesized in the same manner as Example 18 using3H-pyrrolizine-6-carboxylic acid and Example 109. 1H NMR (400 MHz,chloroform-d) δ 7.86-7.61 (m, 2H), 7.40 (d, J=8.3 Hz, 1H), 7.20 (d,J=6.6 Hz, 2H), 7.10 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 6.63 (d,J=6.1 Hz, 1H), 6.44 (s, 1H), 6.34 (d, J=6.1 Hz, 1H), 6.04-5.86 (m, 1H),5.62 (dd, J=15.7, 7.7 Hz, 1H), 4.56 (s, 2H), 4.20-3.94 (m, 3H), 3.82(dd, J=42.9, 13.7 Hz, 3H), 3.58-3.39 (m, 1H), 3.29 (s, 3H), 3.11-2.88(m, 2H), 2.88-2.69 (m, 2H), 2.46 (t, J=30.6 Hz, 4H), 2.16-1.66 (m, 7H),1.28 (s, 2H), 1.13 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₀H₄₅ClN₄O₅S: 729.26; found: 729.30.

Example 136

Step 1: Preparation of methyl 2,3-dihydro-1H-pyrrolizine-6-carboxylate

methyl 3H-pyrrolizine-6-carboxylate (300 mg, 1.85 mmol) and rhodium (5%on alumina) were mixed in ethanol (10 mL). The mixture was degassed,hydrogen gas was injected, and then the mixture was stirred for 5 h. Themixture was filtered through silica and concentrated. Then water wasadded and the mixture was extracted with dichloromethane. The organicphase was dried over anhydrous magnesium sulfate and the solvent wasremoved under reduced pressure to yield methyl2,3-dihydro-1H-pyrrolizine-6-carboxylate. ¹H NMR (400 MHz, chloroform-d)δ 7.21 (d, J=1.4 Hz, 1H), 6.22 (q, J=1.2 Hz, 1H), 3.99-3.86 (m, 2H),3.78 (s, 3H), 2.80 (ddd, J=7.7, 6.7, 1.2 Hz, 2H), 2.48 (tt, J=8.0, 6.8Hz, 2H).

Step 2

2,3-dihydro-1H-pyrrolizine-6-carboxylic acid was synthesized in the samemanner as Example 133 (step 3) using methyl2,3-dihydro-1H-pyrrolizine-6-carboxylate instead of methyl3H-pyrrolizine-6-carboxylate.

Step 3

Example 136 was synthesized in the same manner as Example 18 using2,3-dihydro-1H-pyrrolizine-6-carboxylic acid and Example 109. 1H NMR(400 MHz, chloroform-d) δ 7.76 (d, J=8.5 Hz, 1H), 7.48-7.37 (m, 2H),7.25-7.15 (m, 2H), 7.10 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.35(d, J=1.4 Hz, 1H), 6.05-5.89 (m, 1H), 5.62 (dd, J=15.6, 7.5 Hz, 1H),4.18-3.69 (m, 7H), 3.30 (s, 4H), 3.08-2.94 (m, 1H), 2.92-2.74 (m, 3H),2.61-2.32 (m, 5H), 2.21-1.62 (m, 13H), 1.41 (t, J=12.9 Hz, 1H), 1.13 (d,J=6.8 Hz, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C₄₀H₄₇ClN₄O₅S: 731.30;found: 731.22.

Example 137

Example 137 was synthesized in the same manner as Example 18 using3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylic acid and Example110. 1H NMR (400 MHz, chloroform-d) δ 7.74 (d, J=8.6 Hz, 1H), 7.33 (d,J=1.7 Hz, 1H), 7.21 (dd, J=8.4, 2.5 Hz, 2H), 7.11 (d, J=2.3 Hz, 1H),7.04 (s, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.35 (d, J=1.6 Hz, 1H), 5.99 (d,J=11.2 Hz, 1H), 5.52 (dd, J=15.2, 8.9 Hz, 1H), 4.81 (dd, J=3.3, 1.1 Hz,2H), 4.57 (s, 1H), 4.18-3.96 (m, 3H), 3.92-3.79 (m, 2H), 3.76-3.65 (m,2H), 3.26 (s, 3H), 3.02 (dd, J=15.2, 9.9 Hz, 1H), 2.87-2.70 (m, 3H),2.42 (dt, J=25.8, 9.3 Hz, 3H), 2.29-1.93 (m, 5H), 1.82 (q, J=9.2 Hz,3H), 1.72-1.55 (m, 4H), 1.41 (t, J=12.8 Hz, 1H), 1.28 (s, 2H), 1.01 (d,J=6.2 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₁H₄₉ClN₄O₆S: 761.29;found: 761.22.

Example 138

Example 138 was synthesized in the same manner as Example 18 using1-methyl-1H-pyrazole-4-carboxylic acid and Example 110. 1H NMR (400 MHz,chloroform-d) δ 8.01 (d, J=0.7 Hz, 1H), 7.93 (s, 1H), 7.73 (d, J=8.5 Hz,1H), 7.21 (dd, J=8.5, 2.3 Hz, 1H), 7.18-7.07 (m, 2H), 7.06-6.89 (m, 2H),5.96 (dd, J=15.1, 8.6 Hz, 1H), 5.53 (dd, J=15.2, 9.0 Hz, 1H), 4.67 (d,J=7.3 Hz, 2H), 4.12 (s, 2H), 3.99 (s, 2H), 3.86 (d, J=15.0 Hz, 2H),3.76-3.61 (m, 2H), 3.26 (s, 3H), 3.02 (dd, J=15.2, 10.2 Hz, 2H), 2.79(d, J=15.3 Hz, 3H), 2.41 (dt, J=45.0, 9.2 Hz, 3H), 2.27-1.92 (m, 5H),1.84 (t, J=8.9 Hz, 2H), 1.70-1.58 (m, 3H), 1.41 (t, J=12.4 Hz, 2H), 0.96(d, J=6.2 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₆ClN₅O₅S:720.29; found: 720.23.

Example 139

Example 139 was synthesized in the same manner as Example 18 using3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylic acid and Example109. 1H NMR (400 MHz, chloroform-d) δ 7.74 (d, J=8.5 Hz, 1H), 7.39 (dd,J=15.0, 1.8 Hz, 2H), 7.18 (dd, J=8.4, 2.3 Hz, 2H), 7.10 (d, J=2.3 Hz,1H), 6.95 (d, J=8.3 Hz, 1H), 6.37 (q, J=1.2 Hz, 1H), 5.99 (dt, J=13.7,6.5 Hz, 1H), 5.62 (dd, J=15.6, 7.7 Hz, 1H), 4.84 (d, J=1.1 Hz, 2H),4.18-3.95 (m, 6H), 3.94-3.69 (m, 4H), 3.31 (s, 4H), 3.09-2.95 (m, 2H),2.90-2.68 (m, 2H), 2.59-2.25 (m, 4H), 2.21-2.03 (m, 2H), 2.02-1.82 (m,3H), 1.81-1.60 (m, 3H), 1.41 (t, J=12.7 Hz, 1H), 1.13 (d, J=6.8 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₄₇ClN₄O₆S: 747.29; found: 747.04.

Example 140

The mixture of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid (2.61 mg,0.02 mmol) and Example 109 (8.0 mg, 0.0134 mmol) in DCM (1.0 mL) wascooled to 0° C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (5.11mg, 0.0268 mmol) was added followed by DMAP (3.27 mg, 0.0267 mmol). Thereaction was removed from the cooling bath and stirred at ambient forovernight. The reaction was then concentrated by removing DCM, dilutedwith DMF (1 mL), filtered, and purified by Gilson reverse phase prepHPLC (60-100% ACN/H₂O with 0.1% TFA) to give Example 140. 1H NMR (400MHz, methanol-d4) δ 7.76-7.67 (m, 1H), 7.31 (dd, J=8.2, 1.9 Hz, 1H),7.14-7.04 (m, 3H), 6.86 (d, J=8.2 Hz, 1H), 6.14 (dt, J=14.6, 7.0 Hz,1H), 5.63 (dd, J=15.4, 8.4 Hz, 1H), 4.14 (dd, J=14.8, 6.9 Hz, 1H),4.08-3.93 (m, 3H), 3.88-3.73 (m, 2H), 3.67 (d, J=14.3 Hz, 1H), 3.30 (s,3H), 3.12-2.98 (m, 1H), 2.92-2.70 (m, 3H), 2.59-2.20 (m, 8H), 2.16-2.03(m, 2H), 2.03-1.71 (m, 7H), 1.38 (s, 4H), 1.14 (d, J=6.9 Hz, 3H).LCMS-ESI+ (m/z): calcd [M+H]+ calcd for C₃₈H₄₈ClN₃O₆S: 710.3; found:710.1.

Example 141

Example 141 was synthesized in the same manner as Example 140 usingracemic 1-methyl-4,5,6,7-tetrahydroindazole-6-carboxylic acid instead of3-hydroxy-3-methyl-cyclobutanecarboxylic acid. The later eluted peakfrom reverse phase prep HPLC was arbitrarily assigned as “S”, no actualstereochemistry was determined. 1H NMR (400 MHz, methanol-d4) δ 7.75 (d,J=8.5 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J=8.2, 1.8 Hz, 1H), 7.16 (dd,J=8.5, 2.4 Hz, 1H), 7.10 (dd, J=8.5, 2.1 Hz, 2H), 6.90 (d, J=8.2 Hz,1H), 6.14 (dt, J=14.6, 7.0 Hz, 1H), 5.64 (dd, J=15.4, 8.3 Hz, 1H), 4.15(dd, J=14.8, 7.0 Hz, 1H), 4.11-4.02 (m, 2H), 3.96 (dd, J=14.8, 4.9 Hz,1H), 3.88-3.64 (m, 6H), 3.30 (s, 3H), 3.13-3.02 (m, 1H), 2.99-2.66 (m,6H), 2.65-2.29 (m, 5H), 2.26-2.06 (m, 3H), 2.01-1.69 (m, 8H), 1.51-1.38(m, 1H), 1.18 (d, J=6.9 Hz, 3H). LCMS-ESI+ (m/z): calcd [M+H]C₄₁H₅₀ClN₅O₅S: 760.3; found: 760.1.

Example 142

Example 142 was synthesized in the same manner as Example 140 using3-(1-methylpyrazol-4-yl)propanoic acid instead of3-hydroxy-3-methyl-cyclobutanecarboxylic acid in DMF (1.0 mL) was alsoadded as co-solvent for this reaction). 1H NMR (400 MHz, methanol-d4) δ7.75-7.69 (m, 1H), 7.51 (s, 1H), 7.45-7.41 (m, 1H), 7.31 (dd, J=8.3, 1.9Hz, 1H), 7.14-7.05 (m, 3H), 6.86 (d, J=8.2 Hz, 1H), 6.18-6.06 (m, 1H),5.62 (dd, J=15.5, 8.4 Hz, 1H), 4.14-3.97 (m, 3H), 3.92 (dd, J=14.8, 4.8Hz, 1H), 3.87-3.73 (m, 5H), 3.67 (d, J=14.2 Hz, 1H), 3.30 (s, 3H),3.11-3.00 (m, 1H), 2.90-2.74 (m, 4H), 2.74-2.66 (m, 2H), 2.57-2.38 (m,3H), 2.31-2.19 (m, 1H), 2.14-2.05 (m, 1H), 2.03-1.71 (m, 8H), 1.47-1.36(m, 1H), 1.07 (d, J=6.9 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₉H₄₈ClN₅O₅S 734.35; found: 734.07.

Example 143

Example 143 was synthesized in the same manner as Example 140 usingisochromane-3-carboxylic acid instead of3-hydroxy-3-methyl-cyclobutanecarboxylic acid. The earlier eluted peakfrom reverse phase prep HPLC was arbitrarily assigned as “R”, no actualstereochemistry was determined. 1H NMR (400 MHz, methanol-d4) δ 7.76 (d,J=8.5 Hz, 1H), 7.28 (dd, J=8.2, 1.9 Hz, 1H), 7.25-7.15 (m, 4H),7.14-7.05 (m, 3H), 6.92 (d, J=8.2 Hz, 1H), 6.10 (dt, J=14.5, 6.9 Hz,1H), 5.64 (dd, J=15.4, 8.3 Hz, 1H), 5.06-4.89 (m, 2H) 4.44 (dd, J=9.7,4.7 Hz, 1H), 4.22-4.01 (m, 3H), 3.95 (dd, J=14.9, 5.0 Hz, 1H), 3.85 (d,J=14.9 Hz, 1H), 3.77 (dd, J=8.4, 3.0 Hz, 1H), 3.70 (d, J=14.3 Hz, 1H),3.30 (s, 3H), 3.18-3.02 (m, 3H), 2.90-2.75 (m, 2H), 2.56-2.40 (m, 3H),2.34-2.22 (m, 1H), 2.22-2.07 (m, 2H), 2.00-1.71 (m, 7H), 1.51-1.39 (m,1H), 1.15 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₂H₄₈ClN₃O₆S: 758.37; found: 758.07.

Example 144

Example 109 (350 mg, 0.59 mmol) was dissolved in DCM (5.9 mL) at rt,triethylamine (0.24 g, 2.34 mmol) was added followed byisocyanatocyclopropane (107 mg, 1.3 mmol) in DCM (1 mL). The resultingmixture was stirred at rt for 2 hrs before the reaction was concentratedby removing DCM, the resulting residue was redissolved in EtOAc (30 mL),and washed with 1N HCl (15 mL). The aqueous layer was extracted withEtOAc (2×10 mL). The combined organic layer was washed with saturatedNaHCO₃ (15 mL), brine (15 mL), dried over sodium sulfate, filtered,concentrated, redissolved in DCM, mixed with silica gel, concentrated todryness, and purified by combiflash twice (12 g silica gel, 0-10%DCM/2.0 N NH₃ in MeOH, dry loading). Desired fractions were combined andconcentrated to give Example 144. ¹H NMR (400 MHz, acetone-d₆) δ 7.75(d, J=8.5 Hz, 1H), 7.32-7.05 (m, 4H), 6.84 (d, J=8.2 Hz, 1H), 6.14 (dt,J=14.2, 6.6 Hz, 1H), 5.56 (dd, J=15.4, 8.4 Hz, 1H), 4.04 (q, J=11.9 Hz,3H), 3.85 (d, J=15.1 Hz, 1H), 3.71 (d, J=14.8 Hz, 2H), 3.39 (d, J=14.2Hz, 1H), 3.23 (s, 3H), 3.12 (dd, J=15.0, 9.8 Hz, 1H), 2.89-2.71 (m, 3H),2.69-2.60 (m, 1H), 2.58-2.40 (m, 3H), 2.20-2.10 (m, 3H), 2.00-1.89 (m,3H), 1.83-1.69 (m, 3H), 1.51-1.34 (m, 1H), 1.08 (d, J=6.3 Hz, 3H), 0.66(d, J=6.9 Hz, 2H), 0.56-0.48 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₆H₄₅ClN₄O₅S: 681.28; found: 680.81.

Example 145

Step 1

tert-Butyl but-3-enoate (1.40 mL, 5.75 mmol) was added over 2 min viasyringe to a stirred 9-borabicyclo[3.3.1]nonane solution (0.5 M intetrahydrofuran, 17.2 mL, 9 mmol) at 0° C., and the resulting mixturewas warmed to room temperature. After 4.5 h,5-bromo-1H-pyrrole-3-carbaldehyde (1.00 g, 5.75 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (210 mg,0.287 mmol), potassium carbonate (1.59 g, 11.5 mmol), andN,N-dimethylformamide (30 mL) were added sequentially, and the resultingmixture was heated to 75° C. After 50 min, the reaction mixture washeated to 100° C. After 23 h, the resulting mixture was cooled to roomtemperature, and diethyl ether (400 mL) and saturated aqueous ammoniumchloride solution (50 mL) were added sequentially. The organic layer waswashed with water (2×350 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (0 to 80% ethylacetate in hexanes) to give 145-1.

Step 2

Aqueous lithium hydroxide solution (2.0 M, 11.0 mL, 22 mmol) was addedvia syringe to a vigorously stirred solution of 145-1 (517 mg, 2.18mmol) in tetrahydrofuran (17 mL), water (5.0 mL), and methanol (5.0 mL)at room temperature. After 1 h, the resulting mixture was heated to 70°C. After 3.5 h, the resulting mixture was cooled to room temperature,and aqueous hydrogen chloride solution (2.0 M, 20 mL) and ethyl acetate(100 mL) were added sequentially. The organic layer was washed with amixture of water and brine (1:1 v:v, 2×80 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was dissolved in dichloromethane (24 mL) andN,N-dimethylformamide (4.0 mL), 4-dimethylaminopyridine (400 mg, 3.27mmol) was added, and the resulting mixture was stirred at roomtemperature. After 2 min, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (774 mg, 4.36 mmol) was added. After 14 h, diethyl ether(120 mL) was added. The organic layer was washed sequentially withaqueous hydrogen chloride solution (0.05 M, 100 mL) and water (100 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 80% ethyl acetate in hexanes) to give145-2.

Step 3

A mixture of aqueous sodium chlorite solution (2.0 M, 469 mL, 0.94 mmol)and sodium dihydrogen phosphate monohydrate (120 mg, 0.868 mmol) wasadded via syringe to a vigorously stirred mixture of 145-2 (22 mg, 0.14mmol) and 2-methyl-2-butene (143 mL, 1.35 mmol) in tert-butanol (0.4 mL)at room temperature. After 16.5 h, aqueous hydrogen chloride solution(2.0 M, 20 mL) and ethyl acetate (100 mL) were added sequentially. Theorganic layer was washed with a mixture of water and brine (1:1 v:v,2/80 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to give 145-3.

Step 4: Preparation of Example 145

Example 145 was synthesized in the same manner as Example 18 using 145-3and Example 109. ¹H NMR (400 MHz, acetone-d₆) δ 7.88 (s, 1H), 7.78 (d,J=8.5 Hz, 1H), 7.32-7.21 (m, 2H), 7.19-7.12 (m, 2H), 6.91 (d, J=8.2 Hz,1H), 6.39 (d, J=1.7 Hz, 1H), 6.20-6.06 (m, 1H), 5.60 (dd, J=15.4, 8.4Hz, 1H), 4.11 (d, J=12.1 Hz, 1H), 4.05 (d, J=12.1 Hz, 1H), 3.93-3.65 (m,3H), 3.40 (d, J=14.2 Hz, 1H), 3.24 (s, 3H), 3.24-3.08 (m, 1H), 2.96-1.22(m, 23H), 1.13 (d, J=6.2 Hz, 3H). LCMS-ESI+: calc'd for C₄₁H₄₈ClN₄O₆S:759.3 (M+H); found: 759.0 (M+H).

Example 146

Example 146 was synthesized in the same manner as Example 18 using2-methylthiazole-4-carboxylic acid and Example 109. ¹H NMR (400 MHz,methanol-d₄) δ 8.28 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.22 (dd, J=8.2,1.9 Hz, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.03(d, J=2.0 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.04 (dt, J=14.4, 6.8 Hz,1H), 5.60 (dd, J=15.4, 8.7 Hz, 1H), 4.34 (dd, J=15.0, 6.4 Hz, 1H),4.13-4.03 (m, 2H), 3.98 (dd, J=15.0, 5.7 Hz, 1H), 3.85 (d, J=15.0 Hz,1H), 3.76 (dd, J=8.8, 3.5 Hz, 1H), 3.69 (d, J=14.3 Hz, 1H), 3.33 (s,1H), 3.26 (s, 3H), 3.07 (dd, J=15.3, 10.0 Hz, 1H), 2.77 (s, 3H),2.53-2.35 (m, 3H), 2.24 (tt, J=14.3, 7.2 Hz, 1H), 2.11 (d, J=13.9 Hz,2H), 1.97-1.88 (m, 1H), 1.79 (dt, J=20.3, 8.5 Hz, 2H), 1.49-1.38 (m,1H), 1.29 (s, 1H), 1.11 (d, J=6.7 Hz, 3H). LCMS-ESI+ (m/z): calcd forH+C₃₇H₄₃ClN₄O₅S₂: 723.248; found: 723.221.

Example 147

Example 147 was synthesized in the same manner as Example 18 using1-methyl-1H-pyrrole-3-carboxylic acid and Example 109. ¹H NMR (400 MHz,methanol-d₄) δ 7.74 (d, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.30 (d, J=8.3 Hz,1H), 7.15 (d, J=8.4 Hz, 1H), 7.09 (s, 2H), 6.89 (d, J=8.2 Hz, 1H), 6.72(d, J=2.7 Hz, 1H), 6.66-6.53 (m, 1H), 6.16-6.00 (m, 1H), 5.59 (dd,J=15.3, 8.5 Hz, 1H), 4.23 (dd, J=16.1, 5.8 Hz, 1H), 4.10-3.98 (m, 2H),3.85 (d, J=14.9 Hz, 1H), 3.77 (d, J=8.5 Hz, 1H), 3.72 (s, 3H), 3.68 (d,J=14.3 Hz, 1H), 3.27 (s, 3H), 3.10-3.00 (m, 1H), 2.80 (s, 2H), 2.44 (s,2H), 2.28-2.15 (m, 1H), 2.10 (d, J=15.0 Hz, 1H), 1.76 (s, 2H), 1.49-1.38(m, 1H), 1.29 (s, 2H), 1.12 (d, J=6.5 Hz, 3H). LCMS-ESI+ (m/z): calcdfor H+C₃₈H₄₅ClN₄O₅S: 705.288; found: 705.295.

Example 148

Example 148 was synthesized in the same manner as Example 18 using1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. ¹H NMR (400 MHz,methanol-d₄) δ 7.74 (d, J=8.5 Hz, 1H), 7.17 (t, J=9.6 Hz, 2H), 7.09 (d,J=6.8 Hz, 2H), 6.85 (d, J=7.6 Hz, 1H), 6.35-6.01 (m, 1H), 5.55 (dd,J=15.2, 8.6 Hz, 1H), 4.03 (q, J=12.1 Hz, 2H), 3.84 (d, J=14.9 Hz, 1H),3.78 (d, J=8.6 Hz, 1H), 3.67 (d, J=14.3 Hz, 1H), 3.42 (s, 2H), 3.27 (d,J=1.4 Hz, 3H), 3.11-2.99 (m, 1H), 2.89 (s, 6H), 2.80 (s, 1H), 2.60 (s,0H), 2.43 (s, 2H), 2.23-2.08 (m, 1H), 2.06-1.97 (m, 1H), 1.92 (d, J=10.7Hz, 2H), 1.76 (d, J=6.9 Hz, 3H), 1.42 (t, J=13.0 Hz, 1H), 1.23 (d, J=7.5Hz, 3H), 1.09 (d, J=6.5 Hz, 3H). LCMS-ESI+ (m/z): calcd forH+C₃₇H₄₄ClN₅O₅S: 706.28; found: 706.27.

Example 149

Example 149 was synthesized in the same manner as Example 75 usingExample 109 and cis-3-methoxycyclobutan-1-amine hydrochloride. 1H NMR(400 MHz, Acetone-d6) δ 7.75 (d, J=8.5 Hz, 1H), 7.39 (br s, 1H),7.31-7.15 (m, 2H), 7.10 (s, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.23 (br s,1H), 5.57 (br s, 1H), 4.05 (q, J=10.0 Hz, 2H), 4.00 (m, 2H) 3.88-3.61(m, 4H), 3.44 (d, J=14.4 Hz, 1H), 3.26 (s, 3H), 3.19 (s, 3H), 3.13 (dd,J=15.2, 10.3 Hz, 1H), 2.89-2.68 (m, 2H), 2.67-2.37 (m, 2H), 2.37-2.16(m, 7H), 2.16-2.07 (m, 3H), 1.95 (m, 2H), 1.88 (m, 2H), 1.74 (m, 1H),1.48-1.33 (m, 1H), 1.29 (s, 1H), 1.14 (d, J=6.4 Hz, 3H). LCMS-ESI+:calc'd for C₃₈H₅₀ClN₄O₆S: 725.3 (M+H); found: 724.8 (M+H).

Example 150

Example 150 was synthesized in the same manner as Example 75 usingExample 109 and trans-3-methoxycyclobutan-1-amine hydrochloride. 1H NMR(400 MHz, Acetone-d6) δ 7.64 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H),7.07 (m, 2H), 6.97 (d, J=8.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.16-6.02(m, 1H), 5.67 (dd, J=15.5, 8.3 Hz, 1H), 4.31 (q, J=7.1 Hz, 1H), 4.00 (m,2H) 3.88-3.61 (m, 4H), 3.44 (d, J=14.4 Hz, 1H), 3.26 (s, 3H), 3.19 (s,3H), 3.13 (dd, J=15.2, 10.3 Hz, 1H), 2.89-2.68 (m, 2H), 2.67-2.37 (m,2H), 2.37-2.16 (m, 7H), 2.16-2.07 (m, 3H), 1.95 (m, 2H), 1.88 (m, 2H),1.74 (m, 1H), 1.48-1.33 (m, 1H), 1.29 (s, 1H), 1.14 (d, J=6.4 Hz, 3H).LCMS-ESI+: calc'd for C₃₈H₅₀ClN₄O₆S: 725.3 (M+H); found: 724.5 (M+H).

Example 151

Example 151 was synthesized in the same manner as Example 18 using1-cyclopropyl-1H-pyrazole-4-carboxylic acid and Example 109. LCMS-ESI+(m/z): [M+H]+ calcd for C₃₉H₄₆ClN₅O₅S: 732.3; found: 732.3.

Example 152

Example 152 was synthesized in the same manner as Example 18 using1-(oxetan-3-yl)-1H-pyrazole-4-carboxylic acid and Example 110. ¹H NMR(400 MHz, methanol-d4) δ 8.11 (s, 1H), 7.96 (s, 1H), 7.76 (d, J=8.4 Hz,1H), 7.32 (dd, J=8.0, 2.0 Hz, 1H), 7.17 (dd, J=8.4, 2.4 Hz, 1H), 7.10(d, J=2.4 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H),6.16-6.09 (m, 1H), 5.59-5.50 (m, 2H), 5.05 (d, J=6.8 Hz, 4H), 4.31-4.25(m, 1H), 4.15-4.00 (m, 3H), 3.84 (d, J=14.8 Hz, 1H), 3.78 (d, J=8.4 Hz,1H), 3.62 (d, J=14.4 Hz, 1H), 3.37-3.30 (m, 2H), 3.24 (s, 3H), 3.10-3.04(m, 1H), 2.85-2.72 (m, 2H), 2.47-1.68 (m, 10H), 1.51 (d, J=6.8 Hz, 3H),1.48-1.41 (m, 1H), 1.18 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₄₀H₄₈ClN₅O₆S: 762.3; found: 762.1.

Example 153

Example 153 was synthesized in the same manner as Example 18 using1-ethyl-1H-pyrazole-4-carboxylic acid instead of 3-methoxypropionic acidand Example 110. ¹H NMR (400 MHz, methanol-d4) δ 8.00 (s, 1H), 7.84 (s,1H), 7.72 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.0, 1.6 Hz, 1H), 7.16 (dd,J=8.6, 2.2 Hz, 1H), 7.11 (d, J=2.0 Hz, 2H), 6.77 (d, J=8.0 Hz, 1H),6.15-6.08 (m, 1H), 5.57 (dd, J=15.6, 8.8 Hz, 1H), 4.18 (q, J=7.2 Hz,2H), 4.12 (q, J=7.0 Hz, 2H), 4.07-4.00 (m, 2H), 3.78-3.75 (m, 2H), 3.60(d, J=14.4 Hz, 1H), 3.39-3.33 (m, 2H), 3.25 (s, 3H), 3.16-3.09 (m, 1H),2.86-2.73 (m, 2H), 2.50-1.71 (m, 10H), 1.52-1.44 (m, 7H), 1.21 (d, J=6.8Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for H+C₃₉H₄₈ClN₅O₅S: 734.4;found: 734.2.

Example 154

Example 154 was synthesized in the same manner as Example 18 using3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109.Example 109 (620 mg, 1.04 mmol) was dissolved in dichloromethane (12mL). 3-Methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (324 mg, 2.08mmol, 2 equiv.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (400 mg, 2.08 mmol, 2 equiv.) were added. The reactionmixture was stirred for 5 minutes at room temperature before DMAP (253mg, 2.08 mmol, 2 equiv.) was added in a single portion. The reactionmixture was stirred overnight at room temperature and the progress ofthe reaction was monitored by LCMS. Upon completion, the reactionmixture was concentrated under reduced pressure, and the residue waspurified by Gilson reverse phase prep HPLC (60-100% ACN/H₂O with 0.1%TFA) to give Example 154. ¹H NMR (400 MHz, methanol-d₄) δ 8.07 (s, 1H),7.76 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.22-7.10 (m, 3H), 6.92(d, J=8.2 Hz, 1H), 6.20-6.05 (m, 1H), 5.63 (dd, J=15.5, 8.0 Hz, 1H),4.10 (d, J=12.0 Hz, 1H), 4.06 (s, 4H), 3.91-3.83 (m, 1H), 3.82 (s, 3H),3.79 (s, 1H), 3.72 (d, J=14.4 Hz, 1H), 3.38 (d, J=14.5 Hz, 1H), 3.30 (s,3H), 3.09 (dd, J=15.1, 10.0 Hz, 1H), 2.89-2.72 (m, 2H), 2.51 (d, J=26.7Hz, 2H), 2.24 (dd, J=10.9, 6.0 Hz, 2H), 2.12 (d, J=13.7 Hz, 1H),2.02-1.70 (m, 4H), 1.54-1.40 (m, 1H), 1.14 (d, J=6.1 Hz, 3H). LCMS-ESI+(m/z): calcd for C₃₈H₄₆ClN₅O₆S: 735.28; found: 735.94.

Example 155

Example 155 was synthesized in the same manner as Example 75 usingExample 109 and (3R)-tetrahydrofuran-3-amine. 1H NMR (400 MHz,Methanol-d4) δ 7.73 (d, J=8.4 Hz, 1H), 7.20 (d, J=6.9 Hz, 1H), 7.17-7.09(m, 2H), 6.99 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.10-5.98 (m, 1H), 5.60(dd, J=15.4, 8.8 Hz, 1H), 4.35-4.23 (m, 2H), 4.10-4.01 (m, 2H),3.96-3.75 (m, 6H), 3.72-3.62 (m, 3H), 3.28 (s, 3H), 3.08 (dd, J=15.1,10.2 Hz, 1H), 2.84-2.72 (m, 2H), 2.55-2.37 (m, 3H), 2.32-2.07 (m, 3H),1.97-1.76 (m, 8H), 1.43 (t, J=12.6 Hz, 1H), 1.14 (d, J=6.6 Hz, 3H).LCMS-ESI+ (m/z): calcd H+ for C₃₇H₄₇ClN₄O₆S, Calc'd: 711.29; found:710.79.

Example 156 was synthesized in the same manner as Example 18, usingExample 109 instead of Example 5, and1-cyclopropyl-1H-pyrrole-3-carboxylic acid was used instead of3-methoxypropionic acid. 1H NMR (400 MHz, Methanol-d4) δ 7.76 (d, J=8.5Hz, 1H), 7.62 (t, J=2.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.18 (dd,J=8.5, 2.3 Hz, 1H), 7.15-7.05 (m, 2H), 6.95-6.84 (m, 2H), 6.61 (dd,J=3.0, 1.8 Hz, 1H), 6.11 (dt, J=14.5, 6.8 Hz, 1H), 5.61 (dd, J=15.4, 8.6Hz, 1H), 4.27 (dd, J=14.8, 6.4 Hz, 1H), 4.14-3.94 (m, 3H), 3.87 (d,J=15.1 Hz, 1H), 3.79 (d, J=7.5 Hz, 1H), 3.70 (d, J=14.2 Hz, 1H),3.56-3.46 (m, 1H), 3.36 (s, 1H), 3.29 (s, 3H), 3.08 (dd, J=15.0, 9.4 Hz,2H), 2.89-2.71 (m, 2H), 2.60-2.35 (m, 3H), 2.32-2.06 (m, 3H), 1.94 (d,J=11.6 Hz, 3H), 1.88-1.66 (m, 3H), 1.45 (t, J=12.1 Hz, 1H), 1.13 (d,J=6.7 Hz, 3H), 1.08-0.93 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₀H₄₇ClN₄O₅S: 731.35; found: 729.83.

Example 157

Example 157 was prepared in a similar manner to Example 18 using3,4-dihydro-1H-2-benzopyran-7-carboxylic acid and Example 109. ¹H NMR(400 MHz, Acetonitrile-d₃) δ 7.87 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.71(d, J=8.5 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H),7.16-7.07 (m, 2H), 6.96 (s, 1H), 6.93 (d, J=8.1 Hz, 1H), 5.92 (dt,J=14.2, 6.5 Hz, 1H), 5.55 (dd, J=15.3, 8.9 Hz, 1H), 4.77 (s, 2H), 4.33(dd, J=15.3, 5.6 Hz, 1H), 4.05 (d, J=2.2 Hz, 2H), 3.94 (t, J=5.7 Hz,2H), 3.84-3.64 (m, 3H), 3.26 (d, J=14.3 Hz, 1H), 3.18 (s, 3H), 3.05 (dd,J=15.3, 10.4 Hz, 1H), 2.89 (t, J=5.7 Hz, 2H), 2.84-2.65 (m, 3H),2.50-2.21 (m, 3H), 2.19-2.00 (m, 3H), 1.91-1.81 (m, 3H), 1.79-1.63 (m,3H), 1.47-1.35 (m, 1H), 1.05 (d, J=6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]⁺calculated for C₄₂H₄₈ClN₃O₆S: 758.33; found: 758.0.

Example 158

Example 158 was prepared in a similar manner to Example 18 using1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2-carboxylic acid and Example109. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 9.87 (s, 1H), 7.64 (d, J=8.5Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.09 (s, 1H), 7.06 (d, J=8.7 Hz, 1H),7.01 (s, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.78 (s, 1H), 5.98 (dt, J=13.9,6.5 Hz, 1H), 5.58 (dd, J=15.4, 8.4 Hz, 1H), 4.56 (d, J=2.7 Hz, 2H), 4.13(dd, J=15.0, 5.9 Hz, 1H), 4.00 (s, 2H), 3.87 (t, J=5.6 Hz, 2H),3.82-3.70 (m, 3H), 3.66 (d, J=15.1 Hz, 1H), 3.32 (d, J=14.6 Hz, 1H),3.20 (s, 3H), 3.05 (dd, J=15.3, 10.1 Hz, 1H), 2.84-2.65 (m, 3H), 2.52(dd, J=11.6, 5.3 Hz, 1H), 2.40 (dt, J=16.5, 6.2 Hz, 2H), 2.27-2.08 (m,3H), 2.07-1.98 (m, 1H), 1.91-1.81 (m, 3H), 1.81-1.62 (m, 3H), 1.37 (dt,J=15.1, 7.8 Hz, 1H), 1.06 (d, J=6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]⁺calculated for C₄₀H₄₇ClN₄O₆S: 747.30; found: 747.0.

Example 159

Example 109 (11 mg, 0.018 mmol),(1S,2R)-2-methylcyclopropane-1-carboxylic acid (0.014 mL, 0.147 mmol),diphenyl phosphoryl azide (0.032 mL, 0.147 mmol) and trimethylamine(0.028 mL, 0.202 mmol) were suspended in MeCN (2 mL). The reactionmixture was heated to 50° C. overnight, then cooled to RT. i-PrOAc (10mL) and saturated NH₄Cl (8 mL) were added, and the mixture was stirredfor 10 min. The layers were separated, and the aqueous phase wasextracted with i-PrOAc. The organic phases were combined and washedtwice with water, then dried over MgSO₄, filtered, and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (50% EtOAc/Hex to 40% MeOH/EtOAc) to afford Example 159(6 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.73 (d, J=8.5 Hz, 2H), 7.41 (s,1H), 7.29 (s, 1H), 7.19-7.06 (m, 4H), 6.82 (d, J=8.1 Hz, 2H), 6.17 (s,2H), 5.56 (s, 2H), 4.08-3.95 (m, 3H), 3.86-3.77 (m, 4H), 3.69 (d, J=32.3Hz, 4H), 3.27 (s, 3H), 3.08 (d, J=12.6 Hz, 1H), 2.77 (d, J=21.0 Hz, 3H),2.62 (s, 3H), 2.50 (td, J=7.3, 4.1 Hz, 1H), 2.38 (s, 2H), 2.26 (s, 1H),2.19 (s, 1H), 2.09 (d, J=13.6 Hz, 2H), 1.93 (s, 5H), 1.78-1.70 (m, 2H),1.41 (d, J=13.7 Hz, 1H), 1.29 (s, 1H), 1.06 (dd, J=18.0, 10.9 Hz, 14H),0.89 (ddd, J=15.2, 8.9, 4.2 Hz, 6H), 0.15-0.06 (m, 4H). LCMS-ESI+:calculated for C₃₇H₄₇ClN₄O₅S: 695.3 (M+H); found: 695.2 (M+H).

Example 160

Example 160 was synthesized as a mixture of diastereomers in the samemanner as Example 364, using Example 109 and rac-(1S*,2S*)-2-methoxycyclopropane-1-carboxylic acid. LCMS-ESI+ (m/z): [M+H]⁺ calc'd forC₃₇H₄₇ClN₄O₆S: 711.2978; found: 710.68. ¹H NMR (400 MHz, Methanol-d₄) δ7.72 (dd, J=8.4, 2.3 Hz, 1H), 7.22-7.04 (m, 3H), 7.00-6.84 (m, 2H),6.10-5.92 (m, 1H), 5.58 (dd, J=15.2, 8.9 Hz, 1H), 4.25 (d, J=15.3 Hz,1H), 4.12-3.96 (m, 2H), 3.90-3.71 (m, 3H), 3.66 (d, J=14.3 Hz, 1H), 3.43(d, J=1.8 Hz, 3H), 3.29-3.24 (m, 1H), 3.26 (s, 3H), 3.06 (dd, J=15.2,10.2 Hz, 1H), 2.88-2.69 (m, 2H), 2.62 (s, 1H), 2.55-2.28 (m, 3H),2.26-2.04 (m, 3H), 2.01-1.67 (m, 7H), 1.41 (t, J=12.8 Hz, 1H), 1.12 (d,J=6.5 Hz, 3H), 1.06-0.97 (m, 1H), 0.86-0.76 (m, 1H).

Example 161

Example 161 was synthesized in the same manner as Example 364, usingExample 109 and (1R)-2,2-difluorocyclopropanecarboxylic acid. LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₃₆H₄₃ClF₂N₄O₅S: 717.2684; found: 716.58. ¹HNMR (400 MHz, Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.20-7.07 (m, 3H),7.00-6.86 (m, 2H), 5.98 (dd, J=14.7, 7.7 Hz, 1H), 5.58 (dd, J=15.2, 9.0Hz, 1H), 4.30 (dd, J=15.1, 6.2 Hz, 1H), 4.16-3.98 (m, 2H), 3.92-3.59 (m,4H), 3.29-3.24 (m, 1H), 3.25 (s, 3H), 3.06 (dd, J=15.3, 10.3 Hz, 1H),2.89-2.64 (m, 2H), 2.56-2.25 (m, 3H), 2.26-2.05 (m, 3H), 2.00-1.66 (m,6H), 1.52-1.34 (m, 2H), 1.12 (d, J=6.4 Hz, 3H).

Example 162

Example 162 was prepared in a similar manner to Example 159 using(1R,2S)-2-methylcyclopropane-1-carboxylic acid (0.014 mL, 0.147 mmol),diphenyl phosphoryl azide, triethylamine and Example 109. LCMS-ESI+:calculated for C₃₇H₄₇ClN₄O₅S: 695.3 (M+H); found: 695.2 (M+H).

Example 163

Example 163 was prepared in a similar manner to Example 18 usingpyrrolo[1,2-c]pyrimidine-6-carboxylic acid and Example 109. ¹H NMR (400MHz, Acetonitrile-d₃) δ 8.97 (s, 1H), 8.12 (s, 1H), 7.68 (d, J=8.4 Hz,1H), 7.42 (d, J=6.6 Hz, 1H), 7.36 (d, J=6.5 Hz, 1H), 7.18 (d, J=8.1 Hz,1H), 7.13 (d, J=8.6 Hz, 1H), 7.12 (s, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.91(d, J=8.2 Hz, 1H), 6.85 (s, 1H), 6.03-5.90 (m, 1H), 5.57 (dd, J=15.3,8.6 Hz, 1H), 4.26 (d, J=15.1 Hz, 1H), 4.04 (s, 2H), 3.79 (d, J=15.2 Hz,2H), 3.74-3.64 (m, 2H), 3.30 (d, J=14.3 Hz, 1H), 3.19 (s, 3H), 3.06 (dd,J=15.3, 10.4 Hz, 2H), 2.85-2.66 (m, 3H), 2.52-2.27 (m, 4H), 2.22-2.13(m, 2H), 2.05 (d, J=13.9 Hz, 1H), 1.83-1.64 (m, 3H), 1.39 (dt, J=14.5,7.4 Hz, 1H), 1.09 (d, J=6.1 Hz, 2H). LCMS-ESI+ (m/z): [M+H]⁺ calculatedfor C₄₀H₄₄ClN₅O₅S: 742.28; found: 742.0.

Example 164

Example 164 was synthesized in the same manner as Example 18 using3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. ¹HNMR (400 MHz, Methanol-d₄) δ 8.28 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.28(d, J=8.1 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.86(d, J=8.3 Hz, 1H), 6.19-6.05 (m, 1H), 5.66 (dd, J=15.3, 8.7 Hz, 1H),4.25 (s, 1H), 4.02 (s, 2H), 3.82 (s, 5H), 3.65 (d, J=14.3 Hz, 1H), 3.39(d, J=14.5 Hz, 1H), 3.31 (s, 3H), 3.18-3.03 (m, 1H), 2.90-2.62 (m, 3H),2.52 (d, J=39.0 Hz, 3H), 2.28 (d, J=10.7 Hz, 2H), 2.16-2.04 (m, 2H),1.96 (m, 4H), 1.83 (s, 3H), 1.40 (t, J=12.5 Hz, 1H), 1.18 (d, J=6.2 Hz,3H), 1.01-0.79 (m, 5H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₄₈ClN₅O₅S:746.3; found: 746.0.

Example 165

Example 165 was synthesized in the same manner as Example 18 usingExample 109 and cis-3-hydroxy-3-methyl-cyclobutanecarboxylic acid. 1HNMR (400 MHz, Methanol-d4) δ 7.72 (d, J=9.1 Hz, 1H), 7.31 (dd, J=8.2,1.8 Hz, 1H), 7.09 (dt, J=7.5, 2.0 Hz, 3H), 6.86 (d, J=8.3 Hz, 1H), 6.14(dt, J=14.6, 7.0 Hz, 1H), 5.63 (dd, J=15.4, 8.4 Hz, 1H), 4.14 (dd,J=14.8, 7.0 Hz, 1H), 4.08-3.93 (m, 3H), 3.87-3.74 (m, 2H), 3.67 (d,J=14.3 Hz, 1H), 3.30 (s, 3H), 3.11-3.02 (m, 1H), 2.92-2.70 (m, 3H),2.58-2.23 (m, 8H), 2.15-2.05 (m, 2H), 2.04-1.72 (m, 7H), 1.38 (s, 4H),1.14 (d, J=6.9 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ for C₃₈H₄₈ClN₃O₆S:710.30; found: 710.05.

Example 166

Example 166 was synthesized in the same manner as Example 18 usingExample 110 and cis-3-hydroxy-3-methyl-cyclobutanecarboxylic acid. 1HNMR (400 MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.25-7.15 (m, 2H),7.12 (d, J=2.3 Hz, 1H), 7.10-7.02 (m, 1H), 6.92 (d, J=8.2 Hz, 1H),6.03-5.92 (m, 1H), 5.61 (dd, J=15.3, 8.7 Hz, 1H), 4.38-4.27 (m, 1H),4.13-4.03 (m, 2H), 3.83 (d, J=15.1 Hz, 1H), 3.77-3.71 (m, 1H), 3.68 (d,J=14.3 Hz, 1H), 3.25 (s, 3H), 3.18-3.08 (m, 1H), 2.90-2.71 (m, 3H),2.50-2.20 (m, 9H), 2.16-2.07 (m, 1H), 2.01-1.72 (m, 7H), 1.55 (d, J=7.1Hz, 3H), 1.52-1.41 (m, 1H), 1.38 (s, 3H), 1.14-1.05 (m, 3H). LCMS-ESI+(m/z): calcd H+ for C₃₉H₅₀ClN₃O₆S: 724.31; found: 723.99.

Example 167

Step 1

A vigorously stirred mixture of methyl 5-formyl-1H-pyrrole-3-carboxylate(500 mg, 3.27 mmol), (S)-2-methyloxirane (458 μL, 6.53 mmol), and cesiumcarbonate (2.13 g, 6.53 mmol) in acetonitrile (6.0 mL) and methanol (2.0mL) was heated to 60° C. After 45 min, the reaction mixture was allowedto cool to room temperature, and ethyl acetate (60 mL) was added. Theorganic layer was washed with a mixture of water and brine (1:1 v:v, 40mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 70% ethyl acetate in hexanes) to give167-1.

Step 2

Trifluoroacetic acid (163 μL, 2.13 mmol) was added via syringe to astirred solution of 167-1 (150 mg, 0.710 mmol) in dichloromethane (40mL) at room 0° C. After 2 min, triethylsilane (343 μL, 2.15 mmol) wasadded via syringe, and the resulting mixture was warmed to roomtemperature. After 45 min, triethylamine (1.0 mL) was added via syringe,and the resulting mixture was concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel (0 to40% ethyl acetate in hexanes) to give 167-2.

Step 3

Aqueous sodium hydroxide solution (2.0 M, 800 μL, 1.6 mmol) was addedvia syringe to a stirred solution of 167-2 (53.6 mg, 0.275 mmol) intetrahydrofuran (1.0 mL) and methanol (3.0 mL) at room temperature, andthe resulting mixture was heated to 60° C. After 3 h, the resultingmixture was allowed to cool to room temperature, and aqueous hydrogenchloride solution (2.0 M, 1.0 mL) and ethyl acetate (30 mL) were addedsequentially. The organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to give 167-3.

Step 4: Preparation of Example 167

Example 167 was synthesized in a manner similar to Example 109 using167-3 instead of 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid. 1H NMR(400 MHz, Acetone-d6) δ 7.78 (d, J=8.4 Hz, 1H), 7.45-7.21 (m, 4H), 7.13(d, J=2.3 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.32-5.99 (m, 2H), 5.70-5.58(m, 1H), 4.89 (d, J=14.4 Hz, 1H), 4.71 (d, J=14.3 Hz, 1H), 4.23-3.59 (m,9H), 3.43 (d, J=14.3 Hz, 1H), 3.24 (s, 3H), 3.21-3.10 (m, 1H), 2.85-1.17(m, 19H), 1.12 (d, J=6.8 Hz, 3H). LCMS: 761.0.

Example 168

Example 168 was synthesized in a manner similar to Example 167 using(R)-2-methyloxirane in step 1 instead of (S)-2-methyloxirane. 1H NMR(400 MHz, Acetone-d6) δ 7.79 (d, J=8.5 Hz, 1H), 7.33 (d, J=7.3 Hz, 2H),7.24 (d, J=7.4 Hz, 2H), 7.14 (s, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.27 (s,1H), 6.24-6.11 (m, 1H), 5.59 (dd, J=15.4, 7.9 Hz, 1H), 4.89 (d, J=14.4Hz, 1H), 4.71 (d, J=14.4 Hz, 1H), 4.17-3.59 (m, 9H), 3.42 (d, J=14.4 Hz,1H), 3.24 (s, 3H), 3.13 (dd, J=15.2, 10.4 Hz, 1H), 2.84-1.15 (m, 19H),1.12 (d, J=6.8 Hz, 3H). LCMS: 761.0.

Example 169

Preparation of 3-methoxy-3-methyl-cyclobutanecarboxylic acid:3-hydroxy-3-methyl-cyclobutanecarboxylic acid (116 mg, 0.891 mmol) wasdissolved in DMF (2.0 mL), the resulting solution was cooled to 0° C. Tothis stirred mixture was added 55% sodium hydride dispersion in mineraloil (61.4 mg, 1.47 mmol). The newly formed mixture was stirred at 0° C.for 30 min before Mel (758 mg, 5.37 mmol) was added. The reaction wasthen removed from cooling bath and stirred at room temperature forovernight. The reaction was quenched with ice, partitioned between EtOAc(15.0 mL) and water (5.0 mL). The organic layer was washed with brine(5.0 mL), dried over sodium sulfate, filtered, and concentrated to crudeproduct. The crude product was then dissolved in a mixture of MeOH (2.0mL) and THF (2.0 mL), and treated with 1 N NaOH (4.45 mL, 4.45 mmol).The resulting mixture was heated at 50° C. for 1 hr. The reaction wasconcentrated. The resulting residue was diluted with EtOAc (20.0 mL),acidified with 1N HCl (5.0 mL) and the organic layer was washed withbrine (2×5.0 mL), dried over sodium sulfate, filtered, and concentratedto provide the title compound. 1H NMR (400 MHz, Chloroform-d) δ 3.21 (s,3H), 2.83-2.69 (m, 1H), 2.49-2.41 (m, 2H), 2.23-2.14 (m, 2H), 1.37 (s,3H).

Example 169 was synthesized in a manner similar to Example 18 usingExample 109 and 3-methoxy-3-methyl-cyclobutanecarboxylic acid. 1H NMR(400 MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.3, 1.8Hz, 1H), 7.18-7.13 (m, 1H), 7.10 (dd, J=9.2, 2.1 Hz, 2H), 6.88 (d, J=8.2Hz, 1H), 6.14 (dt, J=14.4, 7.0 Hz, 1H), 5.62 (dd, J=15.4, 8.5 Hz, 1H),4.16 (dd, J=14.8, 6.8 Hz, 1H), 4.10-3.92 (m, 3H), 3.84 (d, J=15.0 Hz,1H), 3.77 (d, J=8.0 Hz, 1H), 3.68 (d, J=14.2 Hz, 1H), 3.30 (s, 3H), 3.21(s, 3H), 3.12-3.01 (m, 1H), 2.96-2.70 (m, 3H), 2.54-2.24 (m, 6H),2.22-2.05 (m, 4H), 2.00-1.72 (m, 7H), 1.39 (s, 4H), 1.14 (d, J=6.9 Hz,3H). [M+H]+ calcd for C₃₉H₅₀ClN₃O₆S: 724.35; found: 724.09.

Example 170

PtO₂ (1.33 mg) was suspended in a solution of Example 144 (20 mg) inEtOH (5.0 mL), one drop of TFA from the tip of the glass pipette wasadded. The atmosphere was exchanged with hydrogen (balloon). The mixturewas stirred for 3 hours. The reaction was degassed and flushed withnitrogen, filtered through Nalgene PTFE filter disc, and concentrated.The resulting residue was then dissolved in DMF (1.2 mL), filtered andpurified by Gilson reverse phase prep HPLC. Desired fractions werecombined and concentrated, retreated with a mixture of ACN/H₂O, andfrozen dried to give Example 170 (6.30 mg). 1H NMR (400 MHz,Methanol-d4) δ 7.77 (d, J=8.5 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.21-7.09(m, 3H), 6.92 (d, J=8.2 Hz, 1H), 4.15-4.02 (m, 3H), 3.88-3.80 (m, 1H),3.68 (d, J=14.2 Hz, 1H), 3.40-3.34 (m, 5H), 3.16-3.07 (m, 1H), 2.88-2.72(m, 2H), 2.68-2.57 (m, 2H), 2.46-2.34 (m, 1H), 2.15-1.86 (m, 5H),1.81-1.61 (m, 4H), 1.60-1.29 (m, 7H), 1.12 (d, J=6.7 Hz, 3H), 0.75 (d,J=7.1 Hz, 2H), 0.60-0.49 (m, 2H). [M+H]+ calcd for C₃₆H₄₇ClN₄O₅S:683.30; found: 682.85.

Example 171

Example 171 was synthesized as a mixture of diastereomers in the samemanner as Example 75, using Example 109 and[rac-(1R*,2R*)-2-aminocyclopropyl]methanol. LCMS-ESI+ (m/z): [M+H]⁺calc'd for C₃₇H₄₇ClN₄O₆S: 711.2978; found: 710.93. ¹H NMR (400 MHz,Methanol-d4) δ 7.72 (d, J=8.5 Hz, 1H), 7.24-7.04 (m, 3H), 6.97 (s, 1H),6.88 (d, J=8.2 Hz, 1H), 6.01 (dd, J=14.9, 7.5 Hz, 1H), 5.58 (dd, J=15.3,8.9 Hz, 1H), 4.24 (dd, J=14.9, 6.5 Hz, 1H), 4.12-3.97 (m, 2H), 3.89-3.71(m, 3H), 3.71-3.60 (m, 1H), 3.51-3.40 (m, 2H), 3.29-3.24 (m, 1H), 3.26(s, 3H), 3.05 (dd, J=15.2, 10.2 Hz, 1H), 2.88-2.67 (m, 2H), 2.56-2.30(m, 4H), 2.26-2.05 (m, 3H), 2.00-1.67 (m, 6H), 1.42 (t, J=12.3 Hz, 1H),1.24-1.16 (m, 1H), 1.12 (d, J=6.5 Hz, 3H), 0.83-0.65 (m, 2H).

Example 172

Example 172 was synthesized in the same manner as Example 75 usingExample 109 and trans-3-amino-1-methylcyclobutan-1-ol HCl salt and DIEA.1H NMR (400 MHz, Methanol-d4) δ 7.67 (d, J=8.5 Hz, 1H), 7.23 (d, J=8.1Hz, 1H), 7.08 (s, 1H), 7.04-6.95 (m, 2H), 6.87 (d, J=8.1 Hz, 1H),6.12-6.01 (m, 1H), 5.71-5.58 (m, 1H), 4.40-4.28 (m, 1H), 4.27-4.15 (m,1H), 4.05-3.99 (m, 2H), 3.85-3.76 (m, 3H), 3.65 (d, J=14.3 Hz, 1H), 3.30(s, 3H), 3.13-3.03 (m, 1H), 2.89-2.70 (m, 2H), 2.63-2.36 (m, 5H),2.33-1.74 (m, 13H), 1.45-1.35 (m, 4H), 1.15 (d, J=6.6 Hz, 3H). LCMS-ESI+(m/z): calcd H+ for C₃₈H₄₉ClN₄O₆S: 725.31; found: 724.80.

Example 173

Example 173 was prepared in a similar manner to Example 18 using3-amino-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. ¹H NMR(400 MHz, Acetonitrile-d₃) δ 8.01 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.15(d, J=8.5 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 7.03 (s, 1H), 6.93 (d, J=2.0Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.04-5.88 (m, 1H), 5.59 (dd, J=15.3,8.8 Hz, 1H), 4.23 (dd, J=19.5, 8.9 Hz, 1H), 4.00 (s, 2H), 3.80-3.71 (m,2H), 3.70 (s, 3H), 3.63 (s, 2H), 3.32 (d, J=14.2 Hz, 1H), 3.20 (s, 3H),3.06 (dd, J=15.3, 10.5 Hz, 1H), 2.88-2.64 (m, 3H), 2.59-2.33 (m, 3H),2.18 (d, J=10.6 Hz, 2H), 2.03 (d, J=13.9 Hz, 2H), 1.91 (d, J=4.1 Hz,1H), 1.84-1.65 (m, 3H), 1.38 (t, J=7.3 Hz, 1H), 1.08 (d, J=6.1 Hz, 3H).LCMS-ESL (m/z): [M+H]⁺ calculated for C₃₇H₄₅ClN₆O₅S: 721.29; found:721.0.

Example 174 Step 1: Preparation of 174-1

A solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylicacid (1.1 g, 6.9 mmol) in DCM (12 mL) was added dropwise oxalyl chloride(1.3 g, 10.41 mmol) and then DMF (0.5 mL). The temperature of themixture was maintained at 0° C. After addition was completed, stirringwas continued at the same temperature for 60 min. Then the solvent wasevaporated under reduced pressure. The resulting residue was dissolvedin a solution of 2-methylpropan-2-ol (1.5 g, 20.8 mmol) in DCM (5 mL)and then stirred at room temperature for 30 min. After reaction wascompleted, the solvent was removed under reduced pressure and purifiedby normal phase chromatography (silica gel column, 0-100% EtOAc/Hexanes)to give 174-1.

Step 2: Preparation of 174-2

174-1 (0.4 g, 1.79 mmol) in ACN (10 mL) at 0° C. was added Selectfluor(0.63 g, 1.79 mmol). The reaction mixture was stirred at 0° C. for 2 h.A saturated aqueous solution of NaHCO₃ was added and the mixture wasextracted with dichloromethane. The organic phase was dried overanhydrous magnesium sulfate, the solvent was removed under reducedpressure, and the residue was purified by normal phase chromatography(silica gel column, 0-100% EtOAc/hexanes) to give 174-2.

Step 3: Preparation of 174-3

174-2 (40 mg, 0.16 mmol) in DMC (4 mL) was added TFA (2 mL) and stirredat rt for 1 h. The reaction mixture was evaporated and used as crude fornext step.

Step 4: Synthesis of Example 174

To a stirred solution of 174-3 (4.6 mg, 0.025 mmol) in DCM (5 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (5.1 mg, 0.033 mmol)and 4-(dimethylamino)pyridine (4 mg, 0.033 mmol) were added. Thereaction mixture was stirred for 10 minutes at room temperature and thenExample 109 (10 mg, 0.017 mmol) was added. The reaction mixture wasstirred at room temperature for 4 hr. Then the reaction mixture wasdiluted with DCM, washed with 1 N HCl and brine. The organic phase wasdried over MgSO₄, filtered, and concentrated to yield Example 174. 1HNMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.5 Hz,2H), 7.24-7.14 (m, 2H), 7.08 (s, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.19 (d,3.9 Hz, 1H), 6.06-5.89 (m, 1H), 5.61 (dd, J=15.5, 7.6 Hz, 1H), 4.74 (s,1H), 4.17-3.99 (m, 3H), 3.98-3.68 (m, 5H), 3.29 (s, 1H), 3.01 (dd,J=15.1, 10.2 Hz, 2H), 2.79 (d, J=15.2 Hz, 2H), 2.59-2.25 (m, 3H),2.19-1.59 (m, 9H), 1.41 (t, J=12.5 Hz, 1H), 1.28 (s, 1H), 1.13 (d, J=6.8Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₄₆ClFN₄O₆S: 765.27;found: 765.25.

Example 175

Step 1

Methyl 7-oxo-5,6,7,8-tetrahydroindolizine-2-carboxylate (50 mg, 0.26mmol) was dissolved in MeOH (2.6 mL) and the reaction mixture was cooledto 0° C. Sodium borohydride (excess) was added in one portion as asolid. The reaction was monitored by TLC. Upon completion, the reactionmixture was concentrated under reduced pressure and the residue waspurified via silica gel chromatography to afford methyl7-hydroxy-5,6,7,8-tetrahydroindolizine-2-carboxylate.

Step 2

Methyl 7-hydroxy-5,6,7,8-tetrahydroindolizine-2-carboxylate (20 mg, 0.1mmol) was dissolved in DMF and sodium hydride (60% oil dispersion, 10mg) was added in one portion. The reaction mixture was stirred for 5 minbefore iodomethane (excess) was added via pipette. The progress of thereaction was monitored by TLC. Upon completion, the reaction mixture wasdiluted with EtOAc. The organic layer was washed with saturated NH₄Cl(1×) followed by brine (2×). The organic layer was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was used in the next step without further purification.

Step 3

Methyl 7-methoxy-5,6,7,8-tetrahydroindolizine-2-carboxylate wasdissolved in 1:1 mixture of dioxane/1 N NaOH. The reaction mixture washeated to 80° C. for 1 hour before it was cooled to room temperature.The reaction mixture was washed with 1 N HCl and diluted with EtOAc. Theorganic layer was separated, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was used in the nextstep without further purification.

Step 4

Example 175 was synthesized in the same manner as Example 18 using7-methoxy-5,6,7,8-tetrahydroindolizine-2-carboxylic acid and Example109. ¹H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J=8.5 Hz, 1H), 7.37 (d,J=8.6 Hz, 1H), 7.31 (t, J=1.8 Hz, 1H), 7.17 (d, J=10.9 Hz, 2H), 7.08 (d,J=2.3 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.36 (s, 1H), 5.98 (dt, J=14.1,6.4 Hz, 1H), 5.59 (dd, J=15.5, 7.6 Hz, 1H), 4.21-3.91 (m, 6H), 3.92-3.71(m, 4H), 3.41 (s, 3H), 3.29 (m, 4H), 3.05-2.68 (m, 5H), 2.56-2.26 (m,5H), 2.13 (m, 4H), 2.01-1.79 (m, 3H), 1.80-1.61 (m, 3H), 1.39 (t, J=12.8Hz, 1H), 1.09 (d, J=6.8 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcd forC₄₂H₅₁ClN₄O₆S: 775; found: 774.9.

Example 176

Example 176 was synthesized in the same manner as Example 18 usingExample 109 and 1-cyclobutyl-1H-pyrazole-4-carboxylic acid. ¹H NMR (400MHz, Methanol-d4) δ 8.21 (s, 1H), 7.97 (s, 1H), 7.79 (d, J=8.5 Hz, 1H),7.28 (dd, J=8.1, 1.7 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.11 (d,J=2.3 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.18 (dt,J=13.9, 6.4 Hz, 1H), 5.49 (dd, J=15.2, 9.3 Hz, 1H), 4.84 (J=8.3 Hz, 1H),4.48 (dd, J=14.0, 6.5 Hz, 1H), 4.09-3.99 (m, 2H), 3.99-3.87 (m, 2H),3.82 (dd, J=9.4, 3.5 Hz, 1H), 3.66 (d, J=14.1 Hz, 1H), 3.29-3.22 (m,4H), 3.02 (dd, J=15.1, 10.0 Hz, 1H), 2.88-2.69 (m, 2H), 2.67-2.45 (m,5H), 2.39 (m, 1H), 2.13 (d, J=13.8 Hz, 1H), 2.09-2.00 (m, 2H), 2.00-1.85(m, 5H), 1.85-1.64 (m, 3H), 1.43 (t, J=12.4 Hz, 1H), 1.04 (d, J=6.0 Hz,3H). LCMS-ESI+: calc'd for C₄₀H₄₉ClN₅O₅S: 746.31 (M+H); found: 746.17(M+H).

Example 177 Step 1

A vigorously stirred mixture of methyl 5-formyl-1H-pyrrole-3-carboxylate(1.50 g, 9.80 mmol), ethylene bromide (10.0 mL, 188 mmol), and potassiumcarbonate (1.62 g, 11.8 mmol) in acetonitrile (20.0 mL) was heated to80° C. After 60 min, the reaction mixture was allowed to cool to roomtemperature and ethyl acetate (60 mL) was added. The organic layer waswashed with a mixture of water and brine (1:1 v:v, 40 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (0 to 35% ethyl acetate in hexanes) to give 177-1.

Step 2

A vigorously stirred mixture of 177-1 (600 mg, 2.31 mmol) and sodiumazide (240 mg, 3.69 mmol) in dimethyl sulfoxide (3.0 mL) was heated to85° C. After 45 min, the resulting mixture was cooled to roomtemperature, and diethyl ether (120 mL) was added. The organic layer waswashed with water (3×100 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL) and stirred at room temperature.Trimethylphosphine solution (1.0 M in tetrahydrofuran, 3.46 mL, 3.5mmol) was added via syringe. After 39 min, the resulting mixture wascooled to 0° C. Sodium borohydride (349 mg, 9.23 mmol) and ethanol (20mL) were added sequentially, and the resulting mixture was allowed towarm to room temperature. After 20 min, diethyl ether (100 mL) wasadded. The organic layer was extracted with a mixture of water and brine(1:1 v:v, 2×100 mL). Tetrahydrofuran (80 mL) and di-tert-butyldicarbonate (1.51 g, 6.92 mmol) were added sequentially to thevigorously stirred combined aqueous layers at room temperature. After 60min, the aqueous layer was extracted with dichloromethane (4×150 mL).The combined organic layers were dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (0 to 50% ethylacetate in hexanes) to give 177-2.

Step 3

Aqueous sodium hydroxide solution (2.0 M, 1.47 mL, 2.9 mmol) was addedvia syringe to a stirred solution of 177-2 (514 mg, 1.83 mmol) inmethanol (2.5 mL) and tetrahydrofuran (3.0 mL) at room temperature, andthe resulting mixture was heated to 70° C. After 2 h, the resultingmixture was cooled to room temperature, and aqueous hydrogen chloridesolution (2.0 M, 5 mL), brine (30 mL), and water (10 mL) were addedsequentially. The aqueous layer was extracted with dichloromethane (2×60mL). The combined organic layers were dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas dissolved in benzene (30 mL), and the resulting mixture wasconcentrated under reduced pressure. The residue was dissolved indichloromethane (6 mL) at room temperature, 2,6-lutidine (854 μL, 7.33mmol) was added via syringe, and the resulting mixture was stirred.Trimethylsilyl trifluoromethanesulfonate (995 μL, 5.50 mmol) was addedvia syringe. After 10 min, methanol (10.0 mL) was added via syringe.After 10 min, the resulting mixture was concentrated under reducedpressure, and the residue was dissolved in benzene (10 mL). Theresulting mixture was concentrated under reduced pressure to give 177-3.

Step 4

Methyl chloroformate (50.5 μL, 791 μmol) was added via syringe to astirred mixture of 177-3 (50.0 mg, 158 μmol) and triethylamine (353 μL,2.53 mmol) in dichloromethane at room temperature. After 10 min,trifluoroacetic acid (0.2 mL) was added, and the resulting mixture waspurified by flash column chromatography on silica gel (0 to 8% methanolin dichloromethane) to give 177-4.

Step 5: Preparation of Example 177

Example 177 was synthesized in a manner similar to Example 109 using177-4 instead of 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid. 1H NMR(400 MHz, Acetone-d6) δ 7.77 (d, J=8.5 Hz, 1H), 7.51 (s, 1H), 7.34 (d,J=8.2 Hz, 1H), 7.29-7.19 (m, 2H), 7.14 (d, J=2.3 Hz, 1H), 6.92 (d, J=8.2Hz, 1H), 6.43 (s, 1H), 6.21-6.07 (m, 1H), 5.64 (dd, J=15.5, 7.9 Hz, 1H),4.66 (s, 2H), 4.17 (s, 2H), 4.11 (d, J=12.0 Hz, 1H), 4.04 (d, J=12.1 Hz,1H), 4.01-3.65 (m, 6H), 3.72 (s, 3H), 3.44 (d, J=14.4 Hz, 1H), 3.25 (s,3H), 3.15 (dd, J=15.2, 10.2 Hz, 1H), 2.89-1.21 (m, 16H), 1.14 (d, J=6.4Hz, 3H). LCMS: 804.0.

Example 178

Example 178 was synthesized in the same manner as Example 18 usingExample 109 and 3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylic acid.1H NMR (400 MHz, Methanol-d4) δ 7.76 (d, J=8.5 Hz, 1H), 7.32 (dd, J=8.2,1.8 Hz, 1H), 7.22-7.15 (m, 1H), 7.14-7.07 (m, 2H), 6.88 (d, J=8.2 Hz,1H), 6.14 (dt, J=14.5, 6.9 Hz, 1H), 5.61 (dd, J=15.3, 8.5 Hz, 1H), 4.17(dd, J=14.7, 6.7 Hz, 1H), 4.11-4.01 (m, 2H), 3.98 (dd, J=14.9, 5.2 Hz,1H), 3.85 (d, J=15.0 Hz, 1H), 3.77 (d, J=8.9 Hz, 1H), 3.69 (d, J=14.3Hz, 1H), 3.29 (s, 3H), 3.11-3.00 (m, 2H), 2.89-2.75 (m, 2H), 2.51-2.40(m, 3H), 2.36-2.23 (m, 4H), 2.18-2.06 (m, 4H), 2.01-1.72 (m, 7H),1.49-1.40 (m, 1H), 1.14-1.09 (m, 9H). LCMS-ESI+ (m/z): calcd H+ forC₄₀H₅₂ClN₃O₆S: 738.33; found: 738.03.

Example 179

Example 179 was synthesized in the same manner as Example 75 usingExample 109 and trans-2-methoxycyclobutanamine HCl salt and DIEA. 1H NMR(400 MHz, methanol-d4) δ 7.77-7.67 (m, 1H), 7.21 (d, J=8.4 Hz, 1H),7.17-7.07 (m, 2H), 6.99 (s, 1H), 6.90 (dd, J=8.1, 3.6 Hz, 1H), 6.11-5.99(m, 1H), 5.60 (t, J=12.5 Hz, 1H), 4.31-4.21 (m, 1H), 4.09-4.01 (m, 3H),3.88-3.64 (m, 6H), 3.28 (s, 3H), 3.08 (dd, J=15.2, 10.1 Hz, 1H),2.89-2.71 (m, 2H), 2.56-2.33 (m, 3H), 2.25-2.02 (m, 6H), 2.02-1.71 (m,7H), 1.59-1.36 (m, 4H), 1.13 (d, J=6.5 Hz, 3H). LCMS-ESI+ (m/z): calcdH+ for C₃₈H₄₉ClN₄O₆S: 725.31; found: 724.85.

Example 180

Step 1

Acetic anhydride (74.7 μL, 791 μmol) was added via syringe to a stirredmixture of 177-3 (50.0 mg, 158 μmol) and triethylamine (353 μL, 2.53mmol) in dichloromethane at room temperature. After 10 min, theresulting mixture was concentrated under reduced pressure. The residuewas purified by reverse phase preparative hplc (0.1% trifluoroaceticacid in acetonitrile/water) to give 180-1.

Step 2

Example 180 was synthesized in a manner similar to Example 109 using180-1 instead of 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid. 1H NMR(400 MHz, Acetone-d6) δ 7.78 (d, J=8.5 Hz, 1H), 7.52 (s, 1H), 7.34 (d,J=8.3 Hz, 1H), 7.28-7.18 (m, 2H), 7.14 (d, J=2.3 Hz, 1H), 6.93 (d, J=8.2Hz, 1H), 6.43 (d, J=1.8 Hz, 1H), 6.19-6.06 (m, 1H), 5.64 (dd, J=15.4,7.9 Hz, 1H), 4.80 (s, 0.92H), 4.69 (s, 1.08H), 4.34-3.60 (m, 10H), 3.44(d, J=14.5 Hz, 1H), 3.25 (s, 3H), 3.15 (dd, J=15.1, 10.2 Hz, 1H),2.90-1.23 (m, 19H), 1.18-1.09 (m, 3H). LCMS: 788.0.

Example 181

Example 181 was synthesized in the same manner as Example 75 usingExample 109 and (1R,2S)-2-tetrahydropyran-4-ylcyclopropanamine HCl saltand DIEA. 1H NMR (400 MHz, Methanol-d4) δ 7.75-7.67 (m, 1H), 7.26-7.16(m, 1H), 7.13-7.05 (m, 2H), 6.99 (s, 1H), 6.89 (d, J=8.2 Hz, 1H),6.12-6.00 (m, 1H), 5.62 (dd, J=15.3, 8.9 Hz, 1H), 4.30-4.19 (m, 1H),4.10-4.00 (m, 2H), 4.00-3.91 (m, 2H), 3.83 (d, J=14.8 Hz, 1H), 3.78 (dd,J=8.9, 3.4 Hz, 1H), 3.67 (d, J=14.2 Hz, 1H), 3.44-3.37 (m, 1H), 3.29 (s,3H), 3.12-3.03 (m, 1H), 2.88-2.73 (m, 2H), 2.57-2.37 (m, 4H), 2.28-2.07(m, 3H), 2.01-1.72 (m, 8H), 1.71-1.62 (m, 1H), 1.57-1.36 (m, 4H), 1.14(d, J=6.6 Hz, 3H), 1.03-0.90 (m, 2H), 0.86-0.75 (m, 1H), 0.75-0.62 (m,2H). LCMS-ESI+ (m/z): calcd H+ for C₄₁H₅₃ClN₄O₆S: 765.34; found: 764.86.

Example 182

Step 1: Preparation of rac-tert-butyl((1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)carbamate

The reaction mixture oftrans-rac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic(70 mg, 0.42 mmol), diphenyl phosphoryl azide (0.095 mL, 0.44 mmol) andtriethylamine (0.065 mL, 0.46 mmol) in toluene (1.0 mL) was heated at100° C. for 2 h. Then the reaction mixture was cooled to rt and to themixture was added t-butanol (0.2 mL, 2 mmol). The mixture was stirred atrt overnight. The reaction mixture was concentrated, and the residue waspurified by silica gel column chromatography (0-100% EtOAc/hexane) togive the product (25 mg).

Step 2: Preparation ofrac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-amine

The reaction mixture of rac-tert-butyl((1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)carbamate (85 mg, 0.36mmol) in DCM (2.0 mL) and TFA (0.5 mL) was stirred at rt. After thereaction was finished, the reaction mixture was concentrated, and theresidue was used in the next step without purification.

Step 3: Preparation of Example 182

The reaction mixture of Example 109 (16 mg, 0.027 mmol), diphenylcarbonate (36 mg, 0.168 mmol) and 4-dimethylaminopyridine (13.07 mg,0.107 mol) in ACN (1.5 mL) was stirred at rt for 7 h. To the mixture wasadded triethylamine (0.19 mL, 1.34 mmol) andrac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropan-1-amine (36.7 mg,0.27 mmol). The reaction mixture was stirred at 45° C. overnight. Thereaction mixture was concentrated, the residue was purified by reversephase HPLC (60-100% CAN/H2O, with 0.1% TFA) to give the product (10 mg).1H NMR (400 MHz, Methanol-d4) δ 7.69 (t, J=8.8 Hz, 1H), 7.37 (d, J=1.9Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.10 (s, 2H), 6.97 (s, 1H), 6.94-6.76(m, 1H), 6.19-5.94 (m, 2H), 5.62 (d, J=13.6 Hz, 1H), 4.38-4.18 (m, 1H),4.13-3.92 (m, 4H), 3.80 (dd, J=22.8, 12.1 Hz, 3H), 3.66 (d, J=14.3 Hz,1H), 3.29 (d, J=3.7 Hz, 3H), 3.08 (dd, J=15.3, 9.9 Hz, 1H), 2.81 (q,J=14.8, 11.3 Hz, 3H), 2.50 (d, J=35.6 Hz, 3H), 2.34-2.14 (m, 2H),2.14-1.87 (m, 5H), 1.80 (d, J=8.1 Hz, 3H), 1.56-1.18 (m, 5H), 1.23-1.03(m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₄₉ClN₆O₅S: 761.32; found:760.53.

Example 183 and Example 184

Example 183 and example 184 were synthesized in the same manner asExample 182, using rac-(1R,2S)-2-(1-methylpyrazol-4-yl)cyclopropanamineinstead of rac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropan-1-amine.The mixture of HPLC purified product was separated by chiral SFCseparation to give example 183 and example 184. The structure for eachcompound was arbitrary assigned.

Example 183

1H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J=8.6 Hz, 1H), 7.45 (s, 1H),7.36 (s, 1H), 7.24-7.09 (m, 3H), 6.99 (s, 1H), 6.91 (d, J=8.2 Hz, 1H),6.02 (s, 1H), 5.59 (dd, J=15.2, 8.9 Hz, 1H), 4.27 (dd, J=15.0, 6.4 Hz,1H), 4.17-4.01 (m, 2H), 3.85 (s, 3H), 3.77 (dd, J=8.9, 3.6 Hz, 2H), 3.68(d, J=14.1 Hz, 1H), 3.27 (s, 3H), 3.08 (dd, J=15.2, 10.2 Hz, 1H),2.89-2.70 (m, 3H), 2.65 (s, 1H), 2.48 (d, J=7.8 Hz, 2H), 2.39 (d, J=9.2Hz, 1H), 2.28-2.08 (m, 3H), 2.08-1.99 (m, 1H), 1.96 (s, 2H), 1.80 (ddd,J=29.3, 20.8, 9.4 Hz, 4H), 1.44 (t, J=12.3 Hz, 1H), 1.34-1.22 (m, 1H),1.14 (s, 3H), 1.04 (q, J=6.3 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₀H₄₉ClN₆O₅S: 761.32; found: 760.96.

Example 184

1H NMR (400 MHz, Methanol-d4) δ 7.71 (d, J=8.3 Hz, 1H), 7.42 (s, 1H),7.34 (s, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.10 (s, 2H), 6.98 (s, 1H), 6.89(d, J=8.2 Hz, 1H), 6.05 (d, J=15.1 Hz, 1H), 5.62 (dd, J=14.8, 8.6 Hz,1H), 4.25 (dd, J=14.5, 6.5 Hz, 1H), 4.18-3.96 (m, 2H), 3.90-3.72 (m,4H), 3.67 (d, J=14.2 Hz, 1H), 3.29 (s, 3H), 3.08 (dd, J=15.1, 10.0 Hz,1H), 2.92-2.70 (m, 2H), 2.66 (dt, J=7.5, 3.9 Hz, 1H), 2.46 (dd, J=30.1,19.3 Hz, 3H), 2.32-2.14 (m, 2H), 2.14-1.93 (m, 4H), 1.93-1.66 (m, 4H),1.50-1.23 (m, 4H), 1.23-1.09 (m, 3H), 1.04 (q, J=6.3 Hz, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C₄₀H₄₉ClN₆O₅S: 761.32; found: 761.90.

Example 185

3-(Ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride(9.6 mg, 0.050 mmol), and 4-(dimethylamino)pyridine (6.1 mg, 0.050 mmol)were added to a solution of 5-formyl-1-methyl-pyrrole-3-carboxylic acid(5.1 mg, 0.033 mmol) in dichloromethane (1 mL). After 5 minutes, Example109 (10 mg, 0.016 mmol) was added. After 17 h the reaction was dilutedwith ethyl acetate (8 mL) and washed with water (5 mL) and saturatedammonium chloride (5 mL). The organic phase was dried over sodiumsulfate and the solvent was removed under reduced pressure. The residuewas taken up in methanol (2 mL), and sodium borohydride (1.0 mg, 0.024mmol) was added. After 3 h the reaction was diluted with ethyl acetate(8 mL) and washed with saturated sodium bicarbonate (5 mL) and saturatedammonium chloride (5 mL). The organic phase was dried over sodiumsulfate. The solvent was removed under reduced pressure. The residue wassubjected to flash chromatography (0-100% ethyl acetate/hexanes followedby 20% methanol/ethyl acetate flush). The clean fractions containingproduct were combined and the solvent was removed under reducedpressure. The residue was co-evaporated with acetonitrile. The residuewas taken up in acetonitrile (2 mL) and water (2 mL). The solution wassubjected to lyophilization, providing Example 185. ¹H NMR (400 MHz,Methanol-d4) δ 7.78 (d, J=8.5 Hz, 1H), 7.44 (d, J=1.9 Hz, 1H), 7.30 (dd,J=8.1, 1.8 Hz, 1H), 7.18 (dd, J=8.5, 2.4 Hz, 1H), 7.11 (d, J=2.3 Hz,1H), 7.07-6.98 (m, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.58 (t, J=1.7 Hz, 1H),6.16 (dt, J=13.9, 6.5 Hz, 1H), 5.53 (dd, J=15.3, 9.0 Hz, 1H), 4.56 (d,J=10.2 Hz, 2H), 4.48-4.30 (m, 1H), 4.12-3.99 (m, 2H), 3.96 (d, J=13.5Hz, 1H), 3.88 (d, J=14.9 Hz, 1H), 3.81 (dd, J=9.0, 3.1 Hz, 1H), 3.72 (d,J=2.1 Hz, 3H), 3.67 (d, J=14.2 Hz, 1H), 3.27 (s, 4H), 3.04 (dd, J=15.1,9.5 Hz, 1H), 2.89-2.69 (m, 2H), 2.57 (m, 1H), 2.51-2.35 (m, 2H), 2.12(d, J=12.1 Hz, 3H), 2.04-1.86 (m, 2H), 1.77 (ddt, J=24.2, 17.1, 9.1 Hz,3H), 1.51-1.35 (m, 1H), 1.07 (d, J=5.9 Hz, 3H), 0.91 (d, J=6.3 Hz, 1H).LCMS-ESI+: calc'd for C₃₉H₄₈ClN₄O₆S: 735.29 (M+H); found: 735.07 (M+H).

Example 186

Example 186 was synthesized in the same manner as Example 75 usingExample 109 and cis-3-amino-1-methylcyclobutan-1-ol and DIEA. 1H NMR(400 MHz, Methanol-d4) δ 7.69 (d, J=9.0 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H),7.10-7.02 (m, 2H), 6.98 (s, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.08-5.97 (m,1H), 5.58 (dd, J=15.4, 8.7 Hz, 1H), 4.26-4.16 (m, 1H), 4.06-3.97 (m,2H), 3.85-3.71 (m, 4H), 3.64 (d, J=14.1 Hz, 1H), 3.26 (s, 3H), 3.09-3.01(m, 1H), 2.86-2.71 (m, 2H), 2.52-2.36 (m, 5H), 2.23-1.90 (m, 9H),1.81-1.70 (m, 3H), 1.45-1.37 (m, 1H), 1.33 (s, 3H), 1.11 (d, J=6.6 Hz,3H). LCMS-ESI+ (m/z): calcd H+ for C₃₈H₄₉ClN₄O₆S: 725.31, Found: 724.78.

Example 187

Example 187 was synthesized in the same manner as Example 18 using3-ethyl-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. ¹H NMR(400 MHz, Methanol-d₄) δ 8.39 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.29 (d,J=8.3 Hz, 1H), 7.06 (s, 1H), 6.98 (d, J=1.9 Hz, 1H), 6.91 (s, 1H), 6.84(d, J=8.2 Hz, 1H), 6.12 (d, J=15.4 Hz, 1H), 5.67 (dd, J=15.4, 8.5 Hz,1H), 4.22 (s, 1H), 4.00 (s, 2H), 3.87 (s, 3H), 3.80 (d, J=10.8 Hz, 2H),3.64 (d, J=14.4 Hz, 1H), 3.41 (d, J=14.5 Hz, 1H), 3.35 (m, 2H), 3.32 (s,3H), 3.11 (dt, J=15.0, 8.3 Hz, 1H), 2.80 (tdd, J=22.6, 15.1, 8.6 Hz,5H), 2.47 (s, 2H), 2.29 (s, 2H), 2.25-2.05 (m, 2H), 1.90 (d, J=47.6 Hz,4H), 1.38 (t, J=12.9 Hz, 1H), 1.26-1.10 (m, 6H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₉H₄₈ClN₅O₅S: 734.3; found: 734.0.

Example 188

Example 188 was synthesized in the same manner as Example 18 using3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid and Example 110. ¹H NMR(400 MHz, Methanol-d₄) δ 7.93 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.18 (dd,J=8.5, 2.5 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 6.99 (d, J=16.9 Hz, 1H),6.93 (d, J=8.2 Hz, 1H), 6.00 (m, 1H), 5.58 (dd, J=15.3, 8.9 Hz, 1H),4.38 (d, J=7.5 Hz, 1H), 4.09 (s, 2H), 3.96 (s, 3H), 3.84 (d, J=15.0 Hz,1H), 3.78 (s, 3H), 3.72 (dd, J=8.9, 3.1 Hz, 1H), 3.66 (d, J=14.3 Hz,1H), 3.35 (m, 2H), 3.24 (s, 3H), 3.17-3.05 (m, 1H), 2.89-2.72 (m, 2H),2.52-2.06 (m, 6H), 2.05-1.70 (m, 6H), 1.60 (d, J=7.0 Hz, 3H), 1.52-1.41(m, 1H), 1.19 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₉H₄₈ClN₅O₆S: 750.3; found: 749.9.

Example 189

Example 189 was synthesized in the same manner as Example 75 usingtrans-(3-aminocyclobutyl)methanol and Example 109. ¹H NMR (400 MHz,Acetone-d₆) δ 7.69 (d, J=8.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.08 (d,J=10.1 Hz, 4H), 6.87 (d, J=8.2 Hz, 1H), 6.08 (d, J=14.8 Hz, 1H),5.72-5.54 (m, 1H), 4.32 (q, J=7.8 Hz, 1H), 4.18-3.95 (m, 3H), 3.90-3.65(m, 4H), 3.60 (d, J=6.7 Hz, 2H), 3.41 (d, J=14.5 Hz, 1H), 3.24 (s, 3H),3.13 (dd, J=15.2, 10.0 Hz, 1H), 2.78 (dt, J=25.3, 16.7 Hz, 2H), 2.51 (d,J=33.4 Hz, 3H), 2.40-1.65 (m, 9H), 1.45-1.35 (m, 1H), 1.13 (d, J=6.2 Hz,3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₅₀ClN₄O₆S: 725.31; found:724.79.

Example 190

Step 1

Methyl 1H-pyrrole-3-carboxylate (1.0 g, 7.99 mmol) was dissolved in DMF(15 mL), and the reaction mixture was cooled to 0° C. via an ice bath.Sodium hydride (480 mg, 60% oil dispersion, 12 mmol, 1.5 equiv.) wasadded portion-wise. The reaction mixture was stirred at that temperaturefor 15 min and then heated to 55° C. for an hour. Tert-butyl4-bromobutanoate (2.23 g, 10 mmol, 1.25 equiv.) was added via syringe.The reaction mixture was heated to 60° C. and progress of the reactionwas monitored by TLC (1:2 EtOAc:Hexanes). Upon completion, the reactionwas cooled to room temperature. The reaction mixture was diluted withEtOAc (100 mL) and washed with water (40 mL) then brine (40 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified via columnchromatography (100% hexanes→1:1 EtOAc:Hexanes) to afford methyl1-(4-(tert-butoxy)-4-oxobutyl)-1H-pyrrole-3-carboxylate.

Step 2

Methyl 1-(4-(tert-butoxy)-4-oxobutyl)-1H-pyrrole-3-carboxylate (1 g, 3.7mmol) was dissolved in a 1:3 solution of trifluoroacetic acid (5 mL) anddichloromethane (15 mL) at room temperature. The reaction mixture wasstirred at room temperature for 24 hours then concentrated under reducedpressure. The residue was azeotroped with toluene (40 mL) to afford4-(3-(methoxycarbonyl)-1H-pyrrol-1-yl)butanoic acid (785 mg, 99%).

Step 3

To a suspension of 4-(3-(m ethoxy carbonyl)-1H-pyrrol-1-yl)butanoic acid(900 mg, 4.26 mmol) and HATU (1620 mg, 4.26 mmol, 1 equiv.) in THF (12mL) was added trimethylamine (1293 mg, 12.78 mmol, 3 equiv.). Thereaction mixture was stirred for 24 hours at room temperature. In aseparate vessel, a suspension of trimethylsulfoxonium chloride (1.64 g,12.78 mmol, 3 equiv.) and potassium tert-butoxide (1.43 g, 12.78 mmol, 3equiv.) were heated to 60° C. via a metal block for 1.5 h. The heatingblock was then removed and the reaction mixture was cooled to 0° C. for15 min via an ice bath. The HATU adduct was then added dropwise viasyringe over 10 min, during which the reaction mixture turned dark red.The reaction mixture was stirred for an additional 1 h at 0° C. beforeit was concentrated under reduced pressure. The crude material waspurified via silica gel chromatography (5% MeOH/DCM) to afford methyl1-(5-(dimethyl(oxo)-λ⁶-sulfanylidene)-4-oxopentyl)-1H-pyrrole-3-carboxylate.

Step 4

Methyl1-(5-(dimethyl(oxo)-λ⁶-sulfanylidene)-4-oxopentyl)-1H-pyrrole-3-carboxylate(315 mg, 1.104 mmol) and Chloro(1,5-cyclooctadiene) Iridium (I) dimer(74 mg, 0.11 mmol, 0.1 equiv.) were dissolved in 1,2-dichloroethane (25mL). The reaction mixture was sparged with an atmospheric stream ofargon for 10 min before it was heated to 80° C. for about 10 min, duringwhich the reaction mixture turned green. The reaction mixture wasconcentrated under reduced pressure and the crude residue was purifiedvia silica gel chromatography for afford methyl8-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2-carboxylate.

Step 5

Methyl 8-oxo-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2-carboxylate(50 mg, 0.24 mmol) was dissolved in MeOH (2.4 mL) and the reactionmixture was cooled to 0° C. Sodium borohydride (excess) was added in oneportion as a solid. The reaction was monitored by TLC. Upon completion,the reaction mixture was concentrated under reduced pressure and theresidue was purified via silica gel chromatography afford methyl8-hydroxy-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2-carboxylate.

Step 6

8-Hydroxy-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2-carboxylate (23mg, 0.11 mmol) was dissolved in DMF and sodium hydride (60% oildispersion, 10 mg) was added in one portion. The reaction mixture wasstirred for 5 min before iodomethane (excess) was added via pipette. Theprogress of the reaction was monitored by TLC. Upon completion, thereaction mixture was diluted with EtOAc. The organic layer was washedwith saturated NH₄Cl (1×) followed by brine (2×). The organic layer wasdried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude residue was used in the next step without furtherpurification.

Step 7

Methyl8-methoxy-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2-carboxylate wasdissolved in 1:1 mixture of dioxane/1 N NaOH. The reaction mixture washeated to 80° C. for 1 hour before it was cooled to room temperature.The reaction mixture was washed with 1 N HCl and diluted with EtOAc. Theorganic layer was separated, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was used in the nextstep without further purification.

Step 8

Example 190 was synthesized in the same manner as Example 18 using8-methoxy-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-2-carboxylic acidand Example 109. LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₃H₅₃ClN₄O₆S: 789.3,found: 789.2.

Example 191

Step 1

Ethyl propiolate (421 μL, 4.16 mmol) was added over 2 min via syringe toa stirred mixture of morpholine-3-carboxylic acid (545 mg, 4.16 mmol)and N,N-diisopropylethylamine (2.17 mL, 12.5 mmol) in tetrahydrofuran(24 mL) and ethanol (16 mL) at room temperature. After 2 h, theresulting mixture was concentrated under reduced pressure. The residuewas dried azeotropically by concentration under reduced pressure fromtoluene (2×20 mL). The residue was dissolved in dichloromethane (77 mL).4-(Dimethylamino)pyridine (254 mg, 2.08 mmol), N,N-diisopropylethylamine(1.59 mL, 9.14 mmol), and triphenylphosphine (1.28 g, 4.86 mmol) wereadded sequentially, and the resulting mixture was stirred and cooled to0° C. Iodine (1.21 g, 4.78 mmol) was added. After 5 min, the resultingmixture was warmed to room temperature. After 33 min, the resultingmixture was heated to 50° C. After 1 h, the resulting mixture was cooledto room temperature, and ethyl acetate (250 mL) was added. The organiclayer was washed sequentially with aqueous hydrogen chloride solution(200 mL) and brine (150 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue wasdissolved in acetone (30 mL), cesium carbonate (5.42 g, 16.6 mmol) wasadded, and the resulting mixture was stirred at room temperature. Methylsulfate (1.97 mL, 20.8 mmol) was added via syringe. After 1 h, theresulting mixture was filtered, and the filter cake was extracted withdichloromethane (75 mL). Silica gel (12 g) was added to the combinedfiltrates, and the resulting slurry was concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (0 to 35% ethyl acetate in hexanes) to give 191-1.

Step 2

Aqueous sodium hydroxide solution (2.0 M, 5.22 mL, 10 mmol) was addedvia syringe to a stirred solution of 191-1 (338.3 mg, 1.50 mmol) inmethanol (1.5 mL) and tetrahydrofuran (1.5 mL) at room temperature, andthe resulting mixture was heated to 70° C. After 1 h, the resultingmixture was cooled to room temperature, and aqueous hydrogen chloridesolution (2.0 M, 6 mL) and brine (20 mL) were added sequentially. Theaqueous layer was extracted sequentially with dichloromethane (2×30 mL)and ethyl acetate (30 mL). The combined organic layers were dried overanhydrous magnesium sulfate, were filtered, and were concentrated underreduced pressure. The residue was purified by reverse phase preparativeHPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give 191-2.

Step 3

Example 191 was synthesized in a manner similar to Example 109 using191-2 instead of 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid. 1H NMR(400 MHz, Acetone-d6) δ 7.79 (d, J=8.5 Hz, 1H), 7.45 (dd, J=8.2, 1.9 Hz,1H), 7.36-7.29 (m, 2H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.14 (d, J=2.3 Hz,1H), 6.92 (d, J=8.2 Hz, 1H), 6.19 (dt, J=14.4, 6.8 Hz, 1H), 5.66 (dd,J=15.6, 7.6 Hz, 1H), 4.97 (d, J=14.1 Hz, 1H), 4.92 (d, J=14.1 Hz, 1H),4.21-3.57 (m, 10H), 3.97 (s, 3H), 3.47 (d, J=14.4 Hz, 1H), 3.26 (s, 3H),3.15 (dd, J=15.1, 11.0 Hz, 1H), 3.02-1.39 (m, 16H), 1.13 (d, J=6.8 Hz,3H). LCMS: 777.0.

Example 192

Example 192 was made in the same sequence as Example 225 except at step1 trans-3-amino-1-methyl-cyclobutanol HCl salt was used. 1H NMR (400MHz, Methanol-d4) δ 7.66 (d, J=8.5 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.08(s, 1H), 7.03-6.95 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 6.12-6.01 (m, 1H),5.70-5.59 (m, 1H), 4.27-4.14 (m, 2H), 4.05-3.99 (m, 2H), 3.84-3.75 (m,3H), 3.66 (d, J=14.3 Hz, 1H), 3.30 (s, 3H), 3.22 (s, 3H), 3.13-3.03 (m,1H), 2.87-2.75 (m, 2H), 2.57-2.43 (m, 5H), 2.26-1.77 (m, 12H), 1.44-1.38(m, 1H), 1.35 (s, 3H), 1.15 (d, J=6.6 Hz, 3H). [M+H]+ calcd forC₃₉H₅₁ClN₄O₆S: 739.36; found: 738.74.

Example 193

Example 193 was made in the same sequence as Example 225 except in step2 iodomethane was used in place of iodoethane. 1H NMR (400 MHz,Methanol-d4) δ 7.72 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.12 (d,J=7.6 Hz, 2H), 6.99 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.04 (dd, J=15.2,7.5 Hz, 1H), 5.61 (dd, J=15.3, 8.9 Hz, 1H), 4.25 (dd, J=15.0, 6.5 Hz,1H), 4.05 (d, J=2.4 Hz, 2H), 3.96-3.73 (m, 4H), 3.67 (d, J=14.3 Hz, 1H),3.28 (s, 3H), 3.20 (s, 3H), 3.08 (dd, J=15.2, 10.1 Hz, 1H), 2.89-2.71(m, 2H), 2.55-2.32 (m, 5H), 2.26-1.91 (m, 9H), 1.80 (dt, J=17.1, 9.2 Hz,3H), 1.43 (t, J=12.0 Hz, 1H), 1.35 (s, 3H), 1.13 (d, J=6.5 Hz, 3H).[M+H]+ calcd for C₃₉H₅₁ClN₄O₆S: 739.36; found: 738.79.

Example 194

Step 1

3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.704 mmol)was dissolved in DMF (3 mL) and sodium hydride (60% dispersion, 84 mg,2.1 mmol, 3 equiv.) was added in one portion. Iodoethane (2.1 mmol, 328mg, 3 equiv.) was added via pipette. The reaction mixture was heated to80° C. until TLC indicated the complete consumption of startingmaterial. The reaction mixture was quenched with saturated NH₄Cl (3 mL)then diluted with EtOAc (10 mL). The organic layer was washed withsaturated NaHCO₃ (10 mL) and brine (10 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified via column chromatography to afford ethyl3-ethoxy-1-methy 1-1H-pyrazole-4-carboxylate.

Step 2

ethyl 3-ethoxy-1-methyl-1H-pyrazole-4-carboxylate (20 mg, 0.1 mmol) wasdissolved in a 1:1 mixture of 1,2-dioxane (1 mL) and 1 N NaOH solution(1 mL). The reaction mixture was heated to 80° C. for 4 hours (reactionmonitored by TLC and LCMS). The reaction mixture was then cooled to roomtemperature and quenched with 1 M HCl (1.5 mL) then diluted with EtOAc(5 mL). The organic layer was washed with saturated NaHCO₃ (5 mL) andbrine (5 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford3-ethoxy-1-methyl-1H-pyrazole-4-carboxylic acid which was used withoutfurther purification.

Step 3

Example 194 was synthesized in the same manner as Example 18 using3-ethoxy-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109.LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₈ClN₅O₆S: 750.3; found: 750.1.

Example 195 and Example 196

Example 195 and Example 196 were purified from Example 160 by chiral SFCseparation and stereochemistry is assigned tentatively.

Example 195

1H NMR (400 MHz, Methanol-d4) δ 7.73 (d, J=8.4 Hz, 1H), 7.19 (d, J=7.7Hz, 1H), 7.12 (d, J=9.0 Hz, 2H), 7.02-6.95 (m, 1H), 6.88 (d, J=8.1 Hz,1H), 6.10-6.01 (m, 1H), 5.59 (dd, J=15.2, 8.8 Hz, 1H), 4.26 (s, 1H),4.04 (d, J=4.7 Hz, 2H), 3.89-3.74 (m, 3H), 3.67 (d, J=14.3 Hz, 1H), 3.45(s, 3H), 3.37 (s, 2H), 3.27 (d, J=4.3 Hz, 3H), 3.07 (dd, J=15.2, 10.2Hz, 1H), 2.87-2.72 (m, 2H), 2.64 (s, 1H), 2.48 (ddd, J=34.7, 22.9, 8.1Hz, 3H), 2.17 (ddd, J=33.0, 21.9, 10.5 Hz, 3H), 1.97 (d, J=14.6 Hz, 3H),1.85-1.72 (m, 3H), 1.43 (t, J=12.3 Hz, 1H), 1.13 (d, J=6.4 Hz, 3H), 1.02(ddd, J=8.9, 6.8, 3.8 Hz, 1H), 0.87-0.79 (m, 1H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₇H₄₇ClN₄O₆S: 711.29; found: 710.76.

Example 196

1H NMR (400 MHz, Methanol-d4) δ 7.76 (d, J=8.5 Hz, 1H), 7.23-7.07 (m,3H), 6.97 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.11-6.02 (m, 1H), 5.56 (dd,J=15.2, 9.0 Hz, 1H), 4.31 (dd, J=14.6, 6.4 Hz, 1H), 4.14-4.00 (m, 2H),3.91-3.74 (m, 3H), 3.67 (d, J=14.1 Hz, 1H), 3.44 (s, 3H), 3.27 (s, 3H),3.21 (s, 1H), 3.06 (dd, J=15.3, 10.3 Hz, 1H), 2.91-2.69 (m, 3H), 2.63(s, 1H), 2.51 (d, J=20.7 Hz, 2H), 2.37 (t, J=8.9 Hz, 1H), 2.14 (t,J=15.4 Hz, 3H), 2.02-1.87 (m, 3H), 1.78 (tt, J=16.9, 9.3 Hz, 3H), 1.43(t, J=12.5 Hz, 1H), 1.12 (d, J=6.3 Hz, 3H), 1.02 (ddd, J=8.8, 6.7, 3.8Hz, 1H), 0.85-0.78 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₇H₄₇ClN₄O₆S: 711.29; found: 710.92.

Example 197

Example 197 was synthesized in the same manner as Example 18, usingExample 109 instead of Example 5 and6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid was usedinstead of 3-methoxypropionic acid. 1H NMR (400 MHz, Methanol-d4) δ 7.77(d, J=8.5 Hz, 1H), 7.26 (dd, J=8.2, 1.9 Hz, 1H), 7.19 (dd, J=8.5, 2.3Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.08 (d, J=1.9 Hz, 1H), 6.95 (d, J=8.2Hz, 1H), 6.09 (t, J=7.3 Hz, 1H), 6.04 (s, 1H), 5.62 (dd, J=15.3, 8.6 Hz,1H), 4.40-4.36 (m, 1H), 4.29 (dt, J=13.4, 6.6 Hz, 2H), 4.15-3.95 (m,3H), 3.90-3.69 (m, 3H), 3.37 (s, 3H), 3.28 (s, 2H), 3.09 (dd, J=15.2,9.7 Hz, 2H), 2.90-2.71 (m, 3H), 2.47 (s, 3H), 2.33 (p, J=5.9 Hz, 2H),2.28-2.08 (m, 3H), 1.95 (d, J=3.7 Hz, 3H), 1.79 (q, J=11.1, 9.0 Hz, 3H),1.46 (t, J=13.1 Hz, 1H), 1.12 (d, J=6.7 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₉H₄₆ClN₅O₆S: 748.29; found: 746.89.

Example 198

Example 198 was synthesized in the same manner as Example 18 using3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxylic acid and Example109. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.73 (d, J=8.5 Hz, 1H), 7.25(dd, J=8.2, 1.9 Hz, 1H), 7.19 (dd, J=8.4, 2.3 Hz, 1H), 7.15 (d, J=2.3Hz, 1H), 7.09 (d, J=1.9 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.04 (dt,J=14.5, 6.9 Hz, 1H), 5.60 (dd, J=15.4, 8.3 Hz, 1H), 4.14-3.96 (m, 3H),3.88-3.64 (m, 4H), 3.33 (d, J=14.3 Hz, 1H), 3.23 (s, 3H), 3.04 (dq,J=17.7, 9.3, 8.7 Hz, 2H), 2.87-2.66 (m, 4H), 2.46 (dq, J=24.9, 8.8, 7.2Hz, 4H), 2.06 (s, 4H), 1.91 (t, J=4.9 Hz, 3H), 1.84-1.63 (m, 4H), 1.42(dt, J=14.9, 7.7 Hz, 1H), 1.09 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₈H₄₅ClF₃N₃O₆S: 764.26; found: 764.09.

Example 199

Example 199 was synthesized in the same manner as Example 75 usingExample 109 and trans-ethylcyclopropan-1-amine hydrochloride. ¹H NMR(400 MHz, Methanol-d4) δ 7.77 (d, J=8.5 Hz, 1H), 7.18 (dd, J=8.4, 2.5Hz, 2H), 7.11 (d, J=2.3 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J=8.1 Hz, 1H),6.20-6.04 (m, 1H), 5.52 (dd, J=15.2, 9.1 Hz, 1H), 4.30 (d, J=14.3 Hz,1H), 4.12-3.98 (m, 2H), 3.87 (d, J=15.0 Hz, 1H), 3.80 (dd, J=9.1, 3.4Hz, 1H), 3.66 (d, J=14.1 Hz, 1H), 3.27 (s, 4H), 3.03 (dd, J=15.2, 9.9Hz, 1H), 2.88-2.70 (m, 2H), 2.55 (m, 1H), 2.42 (m, 1H), 2.32 (s, 1H),2.22 (dt, J=7.0, 3.4 Hz, 1H), 2.12 (d, J=12.4 Hz, 3H), 2.03-1.85 (m,2H), 1.77 (ddt, J=25.7, 17.3, 9.2 Hz, 3H), 1.40 (dd, J=14.0, 70 Hz, 2H),1.23 (dt, J=14.5, 7.2 Hz, 1H), 1.12-1.06 (m, 3H), 1.04 (d, J=2.7 Hz,1H), 1.02 (d, J=2.7 Hz, 2H), 1.00 (d, J=2.8 Hz, 1H), 0.89-0.77 (m, 1H),0.69-0.55 (m, 2H), 0.50 (m, 2H). LCMS-ESI+: calc'd for C₃₈H₅₀ClN₄O₅S:709.31 (M+H); found: 709.38 (M+H).

Example 200

Example 189 (6.0 mg) was treated with sodium hydride (75.0 mg, 60%dispersion in mineral oil) and iodomethane (12 mg, 0.008 mmol, 10equiv.) in THF at rt. The reaction mixture was quenched with water (30mL) and the whole was extracted with EtOAc (30 mL). Obtained organiclayer was washed with brine (30 mL) and dried over Na₂SO₄. The solventwas removed under a reduced pressure. Obtained crude mixture waspurified by a silica-gel preparative TLC (5% MeOH/DCM, developed twice)to give Example 200. 1H NMR (400 MHz, Acetone-d₆) δ 7.74 (d, J=8.5 Hz,1H), 7.39-7.08 (m, 4H), 6.92-6.84 (m, 1H), 6.13-6.03 (m, 1H), 5.55-5.64(m, 1H), 4.36-4.24 (m, 1H), 4.12-4.00 (m, 2H), 3.88-3.77 (m, 1H), 3.71(d, J=14.6 Hz, 2H), 3.40 (d, J=7.0 Hz, 2H), 3.31 (s, 3H), 3.23 (s, 3H),3.00-2.10 (m, 19H), 2.00-1.64 (m, 4H), 1.50-1.40 (m, 1H), 1.11 (d, J=6.3Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₅₂ClN₄O₆S: 739.32; found:738.65.

Example 201

Intermediate 201-1 was prepared in similar manner to Example 109-Method1 using(2S)—N′-(tert-butyldimethylsilyl)-2-ethylpent-4-ene-1-sulfonimidamide(prepared from (S)-2-ethylpent-4-ene-1-sulfonamide) instead of(4S)-5-[S-amino-N-[tert-butyl(dimethyl)silyl]sulfonimidoyl]-4-methyl-pent-1-ene.¹H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.5 Hz, 1H), 7.43 (dd,J=8.2, 1.9 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.5, 2.4 Hz,1H), 7.10 (d, J=2.3 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.33 (dt, J=14.8,7.1 Hz, 1H), 5.89 (s, 2H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.11-4.01 (m,2H), 3.87 (d, J=14.7 Hz, 1H), 3.84-3.75 (m, 1H), 3.71 (dd, J=8.5, 3.9Hz, 1H), 3.61 (dd, J=14.5, 3.6 Hz, 1H), 3.42 (d, J=9.5 Hz, 1H), 3.39 (d,J=9.5 Hz, 1H), 3.27 (s, 3H), 3.01 (dd, J=15.0, 11.1 Hz, 1H), 2.88-2.71(m, 2H), 2.58 (d, J=9.6 Hz, 1H), 2.46 (dq, J=20.6, 10.6, 9.1 Hz, 1H),2.32 (dt, J=14.3, 6.9 Hz, 1H), 2.07 (s, 2H), 1.99-1.85 (m, 1H), 1.74(dq, J=33.7, 9.2, 8.8 Hz, 2H), 1.50 (t, J=7.2 Hz, 2H), 1.42 (q, J=13.3,12.9 Hz, 1H), 0.96 (t, J=7.4 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₃H₄₂ClN₃O₄S: 612.3; found: 612.5.

Example 201 was synthesized in the same manner as Example 18 usingintermediate 201-1 and 1-methyl-1H-pyrazole-4-carboxylic acid. ¹H NMR(400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.94 (d, J=0.6 Hz, 1H), 7.79 (d,J=8.5 Hz, 1H), 7.24 (dd, J=8.0, 1.7 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz,1H), 7.11 (d, J=2.3 Hz, 1H), 6.93 (d, J=1.9 Hz, 1H), 6.83 (d, J=8.1 Hz,1H), 6.17 (ddd, J=14.6, 9.0, 5.1 Hz, 1H), 5.48 (dd, J=15.3, 9.3 Hz, 1H),4.50 (dd, J=14.1, 9.3 Hz, 1H), 4.11-3.96 (m, 3H), 3.95-3.86 (m, 4H),3.82 (dd, J=9.4, 3.8 Hz, 1H), 3.67 (d, J=14.1 Hz, 1H), 3.25 (m, 4H),3.00 (dd, J=15.2, 10.1 Hz, 1H), 2.90-2.75 (m, 2H), 2.71 (d, J=15.0 Hz,1H), 2.53-2.41 (m, 1H), 2.37 (m, 1H), 2.19-2.05 (m, 2H), 2.05-1.82 (m,4H), 1.82-1.64 (m, 2H), 1.49-1.27 (m, 4H), 0.90 (t, J=7.4 Hz, 3H).LCMS-ESI+: calc'd for C₃₈H₄₇ClN₅O₅S: 720.19 (M+H); found: 720.31 (M+H).

Example 202

Example 202 was synthesized in the same manner as Example 18 usingintermediate 201-1 and3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylic acid. ¹H 1H NMR(400 MHz, Methanol-d4) δ 7.77 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.28 (d,J=8.2 Hz, 1H), 7.16 (d, J=8.9 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 7.01 (s,1H), 6.87 (d, J=8.1 Hz, 1H), 6.34 (s, 1H), 6.15 (d, J=7.8 Hz, 1H),5.61-5.49 (m, 1H), 4.78 (s, 2H), 4.34 (s, 1H), 4.04 (m, 6H), 3.87 (d,J=15.0 Hz, 1H), 3.83-3.75 (m, 1H), 3.68 (d, J=14.2 Hz, 1H), 3.27 (s,3H), 3.04 (dd, J=15.1, 9.4 Hz, 1H), 2.79 (m, 2H), 2.68 (m, 1H), 2.41 (m,2H), 2.24 (m, 1H), 2.12 (m, 1H), 1.98 (m, 3H), 1.86-1.64 (m, 3H),1.57-1.38 (m, 2H), 0.33 (m, 4H), 0.94 (t, J=7.3 Hz, 3H). LCMS-ESI+:calc'd for C₄₁H₅₀ClN₄O₆S: 761.31 (M+H); found: 761.34 (M+H).

Example 203

Example 203 was prepared in a similar manner to Example 18 using4-methylfuran-2-carboxylic acid and Example 109. ¹H NMR (400 MHz,Acetone-d₆) δ 7.75 (d, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.31-7.15 (m, 3H),7.12 (d, J=2.5 Hz, 2H), 6.93 (d, J=8.2 Hz, 1H), 6.04 (dd, J=14.7, 7.3Hz, 1H), 5.61 (dd, J=14.8, 8.8 Hz, 1H), 4.17-3.99 (m, 2H), 3.88 (d,J=15.0 Hz, 2H), 3.80-3.68 (m, 2H), 3.38 (d, J=14.3 Hz, 1H), 3.22 (s,3H), 3.14 (dd, J=15.1, 9.9 Hz, 1H), 2.93-2.67 (m, 2H), 2.61-2.36 (m,3H), 2.33-2.18 (m, 2H), 2.16-2.07 (m, 3H), 2.08 (s, 3H) 2.00-1.85 (m,2H), 1.84-1.65 (m, 3H), 1.46 (dt, J=15.2, 7.5 Hz, 1H), 1.14 (d, J=6.2Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₅ClN₃O₆S: 706.26; found:705.95.

Example 204

Example 204 was prepared in a similar manner to Example 18 using5-methylfuran-3-carboxylic acid and Example 109. ¹H NMR (400 MHz,Acetone-d₆) δ 8.09 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.20 (dt, J=8.4, 3.2Hz, 2H), 7.15-7.05 (m, 2H), 6.92 (d, J=8.2 Hz, 1H), 6.43 (s, 1H), 6.06(dt, J=14.3, 6.6 Hz, 1H), 5.61 (dd, J=15.5, 8.5 Hz, 1H), 4.27 (d, J=15.9Hz, 1H), 4.15-4.00 (m, 2H), 3.85 (t, J=15.3 Hz, 2H), 3.77-3.67 (m, 2H),3.38 (d, J=14.3 Hz, 1H), 3.22 (s, 3H), 3.13 (dd, J=15.3, 9.9 Hz, 1H),2.91-2.68 (m, 2H), 2.49 (d, J=20.3 Hz, 4H), 2.31 (d, J=1.1 Hz, 3H),2.29-2.07 (m, 3H), 2.09 (s, 4H), 2.02-1.89 (m, 3H), 1.77 (ddt, J=25.6,15.2, 7.9 Hz, 3H), 1.45 (dt, J=15.0, 7.6 Hz, 1H), 1.14 (d, J=6.5 Hz,3H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₈H₄₅ClN₃O₆S: 706.26; found:706.06.

Example 205 Step 1

A solution of methyl 1H-pyrrole-3-carboxylate (4.3 g, 0.034 mol) in dryDMF (10 mL) was added dropwise, under nitrogen atmosphere, to a stirredsuspension of NaH 60% (oil dispersion) (1.6 g, 0.041 mol) in dry DMF (40mL). The temperature of the mixture was maintained at 0° C. Afteraddition was completed, stirring was continued at the same temperaturefor 30 min. Then a solution of tert-butyl 2-bromoacetate (10.1 g, 0.052mol) was added dropwise and the temperature was allowed to rise to roomtemperature. The reaction mixture was stirred at this temperature for 48h. Then water was added and the mixture extracted with dichloromethane.The organic phase was dried over anhydrous magnesium sulfate and thesolvent was removed under reduced pressure, then the residue waspurified by normal phase chromatography (silica gel column, 0-100%EtOAc/Hexanes) to give 205-1.

Step 2

A solution of 205-1 (7.2 g, 0.30 mol) in DCM (45 mL) was added TFA (15mL) and stirred at room temperature overnight. Then water was added andlayers were separated. The organic phase was dried over anhydrousmagnesium sulfate and the solvent was removed under reduced pressure togive 205-2.

Step 3

A suspension of 205-2 (4.3 g, 0.023 mol) and HATU (8.9 g, 0.023 mol) inTHF (60 mL) was treated with TEA (7.2 mL, 0.070 mol) and the resultingsolution was stirred at rt for about 16 h. Separately, a suspension ofpotassium tert-butoxide (7.4 g, 0.066 mol) and trimethylsulfoxoniumchloride (8.4 g, 0.066 mol) in THF (70 mL) was heated at about 60° C.for about 2 h, and then cooled in an ice-water bath for about 15 min.The solution of activated ester was then added drop-wise at about 0° C.over a period of about 45 min. The reaction mixture was further stirredfor about 1 h, after which the reaction was concentrated under reducedpressure. The residue was partitioned between DCM and water. Afterseparating the layers, the organic phase was washed with saturatedaqueous NaCl, dried over Mg₂SO₄, filtered, and concentrated underreduced pressure. The crude material was purified on silica gel (80 g)using a gradient of 0-100% EtOAc in hexanes. A solution of activatedacid and chloro(1,5-cyclooctadiene)iridium(I) dimer (60 mg) in DCE (80mL) was degassed. The mixture was heated in uw at about 80° C. for about10 min, and then cooled to rt. The reaction mixture was concentratedunder reduced pressure. The residue was purified on silica gel 5-80%EtOAc in hexanes to give 205-3.

Step 4

To a stirred solution of 205-3 (50 mg, 0.27 mmol) in methanol (5 mL) at0° C. was added in small portions NaBH₄ (11 mg, 0.27 mmol) and stirredat 0° C. for 1 h and diluted with a 10% aqueous ammonium chloridesolution. The organic solvent was removed using an evaporator. Theremaining aqueous solution was subjected to two extractions with ethylacetate. The organic layer was washed with saturated brine, then driedover sodium sulfate and then concentrated. The residue was purified byreverse phase chromatography ACN/Water 15-90% for 15 min with 0.1% TFAto give 205-4.

Step 5: Preparation of 205-5

To a stirred solution of 205-4 (32 mg, 0.17 mmol) in DMF (3 mL) wasadded NaH 60% (7 mg, 0.17 mmol) and stirred at room temperature for 1 h.The reaction mixture was subjected to two extractions with DCM. Theorganic layer was washed with saturated brine, then dried over sodiumsulfate and then concentrated. The residue was used on next step.

Step 6

To a stirred solution of 205-5 (30 mg, 0.15 mmol) in methanol (3 mL) wasadded 1N of NaOH (1 mL) and stirred at rt for 1 h. To the reactionmixture was added 1N HCl (1 mL) and the reaction mixture wasconcentrated. Water was added and the mixture was extracted withdichloromethane. The organic phase was dried over anhydrous magnesiumsulfate and the solvent was removed under reduced pressure to give205-6.

Step 7

Example 205 was synthesized in the same manner as Example 174 usingintermediate 205-6 and Example 109. ¹H NMR (400 MHz, Chloroform-d) δ7.75 (dd, J=8.5, 1.7 Hz, 1H), 7.46-7.35 (m, 2H), 7.19 (d, J=9.2 Hz, 2H),7.10 (d, J=2.2 Hz, 1H), 6.95 (dt, J=8.2, 1.5 Hz, 1H), 6.38 (s, 1H), 6.00(dt, J=13.6, 6.4 Hz, 1H), 5.62 (dd, J=15.6, 7.6 Hz, 1H), 4.57 (dt,J=6.1, 3.0 Hz, 1H), 4.21 (ddd, J=11.9, 5.9, 2.5 Hz, 1H), 4.14-3.95 (m,3H), 3.93-3.65 (m, 3H), 3.43 (s, 3H), 3.31 (s, 3H), 3.20-2.66 (m, 5H),2.58-2.26 (m, 3H), 2.19-1.61 (m, 6H), 1.28 (m, 5H), 1.12 (d, J=6.8 Hz,3H), 0.95-0.63 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₁H₄₉ClN₄O₆S:761.31; found: 761.59.

Example 206

Example 206 was synthesized in the same manner as Example 75 using(1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-amine and Example 109. ¹H NMR (400MHz, Methanol-d₄) δ 7.73 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.13(d, J=14.6 Hz, 2H), 6.97 (s, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.03 (d,J=14.8 Hz, 1H), 5.60 (dd, J=15.2, 8.9 Hz, 1H), 4.26 (br, 1H), 4.06 (m,2H), 3.98 (d, J=8.5 Hz, 2H), 3.84 (d, J=15.0 Hz, 1H), 3.81-3.71 (m, 3H),3.67 (d, J=14.2 Hz, 1H), 3.35-3.32 (m, 4H), 3.27 (s, 3H), 3.07 (dd,J=15.2, 10.3 Hz, 1H), 2.89-2.71 (m, 2H), 2.45 (d, J=28.6 Hz, 4H),2.29-2.06 (m, 3H), 2.03-1.69 (m, 5H), 1.43 (t, J=12.8 Hz, 1H), 1.14 (d,J=6.5 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₇ClN₄O₆S: 723.3;found: 722.9.

Example 207

Example 207 was synthesized in the same manner as Example 75 usingExample 109 and trans-2-(difluoromethyl)cyclopropan-1-aminehydrochloride. ¹H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H),7.16 (d, J=8.1 Hz, 2H), 7.11 (d, J=2.3 Hz, 1H), 6.97 (s, 1H), 6.92 (d,J=8.2 Hz, 1H), 6.08-5.99 (m, 1H), 5.99-5.67 (m, 1H), 5.59 (dd, J=15.3,8.9 Hz, 1H), 4.33-4.22 (m, 1H), 4.11-4.01 (m, 2H), 3.85 (d, J=15.1 Hz,1H), 3.77 (dd, J=9.0, 3.7 Hz, 1H), 3.68 (d, J=14.3 Hz, 1H), 3.27 (s,4H), 3.08 (dd, J=15.3, 10.3 Hz, 1H), 2.79 (ddd, J=22.7, 17.7, 9.6 Hz,3H), 2.48 (d, J=8.1 Hz, 2H), 2.37 (t, J=8.3 Hz, 1H), 2.28-2.04 (m, 3H),2.04-1.88 (m, 2H), 1.79 (m, 2H), 1.69-1.49 (m, 1H), 1.44 (t, J=12.9 Hz,1H), 1.33 (d, J=17.3 Hz, 2H), 1.14 (d, J=6.4 Hz, 3H), 1.09 (q, J=6.4 Hz,1H), 0.95 (m, 2H). LCMS-ESI+: calc'd for C₃₇H₄₆ClF₂N₄O₅S: 731.28 (M+H);found: 731.05 (M+H).

Example 208 and Example 209

Step 1

methyl 1H-pyrrole-3-carboxylate (2.0 g, 15.98 mmol) was dissolved inacetonitrile (30 mL), and tert-butyl acrylate (2.46 g, 19.18 mmol, 1.2equiv.) was added via syringe. 1,8-diazabicyclo[5.4.0]undec-7-ene (2.43g, 15.98 mmol, 1 equiv.) was added dropwise at room temperature over 2min. The reaction mixture was heated to 80° C. and progress of thereaction was monitored by TLC (1:2 EtOAc:Hexanes). Upon completion, thereaction was cooled to room temperature and concentrated under reducedpressure. The residue was diluted with EtOAc (40 mL) and washed withsaturated ammonium chloride (40 mL) then brine (40 mL). The organiclayer was dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified via column chromatography(100% hexanes→1:1 EtOAc:Hexanes) to afford methyl1-(3-(tert-butoxy)-3-oxopropyl)-1H-pyrrole-3-carboxylate (4.05 g, 94%).

Step 2

methyl 1-(3-(tert-butoxy)-3-oxopropyl)-1H-pyrrole-3-carboxylate (3.8 g,15 mmol) was dissolved in a 1:3 solution of trifluoroacetic acid (10 mL)and dichloromethane (30 mL) at room temperature. The reaction mixturewas stirred at room temperature for 24 hours then concentrated underreduced pressure. The residue was azeotroped with toluene (40 mL) toafford 3-(3-(methoxycarbonyl)-1H-pyrrol-1-yl)propanoic acid (2.95 g,99%).

Step 3

To a suspension of 3-(3-(methoxycarbonyl)-1H-pyrrol-1-yl)propanoic acid(2.00 g, 10.14 mmol) and HATU (3.86 g, 10.14 mmol, 1 equiv.) in THF (30mL) was added trimethylamine (3.91 g, 30.43 mmol, 3 equiv.). Thereaction mixture was stirred for 24 hours at room temperature. In aseparate vessel, a suspension of trimethyl sulfoxonium chloride (3.91 g,30.43 mmol, 3 equiv.) and potassium tert-butoxide (3.41 g, 30.43 mmol, 3equiv.) were heated to 60° C. via a metal block for 1.5 h. The heatingblock was then removed, and the reaction mixture was cooled to 0° C. for15 min via an ice bath. The HATU adduct was then added dropwise viasyringe over 10 min, during which the reaction mixture turned dark red.The reaction mixture was stirred for an additional 1 h at 0° C. beforeit was concentrated under reduced pressure. The crude material waspurified via silica gel chromatography (5% MeOH/DCM) to afford methyl1-(4-(dimethyl(oxo)-λ⁶-sulfanylidene)-3-oxobutyl)-1H-pyrrole-3-carboxylate.

Step 4

Methyl1-(4-(dimethyl(oxo)-λ⁶-sulfanylidene)-3-oxobutyl)-1H-pyrrole-3-carboxylate(150 mg, 0.553 mmol) and chloro(1,5-cyclooctadiene) Iridium (I) dimer(37 mg, 0.00553 mmol, 0.1 equiv.) were dissolved in 1,2-dichloroethane(15 mL). The reaction mixture was sparged with an atmospheric stream ofargon for 10 min before it was heated to 80° C. for about 10 min, duringwhich the reaction mixture turned green. The reaction mixture wasconcentrated under reduced pressure and the crude residue was purifiedvia silica gel chromatography for afford methyl7-oxo-5,6,7,8-tetrahydroindolizine-2-carboxylate.

Step 5

Methyl 7-oxo-5,6,7,8-tetrahydroindolizine-2-carboxylate (40 mg, 0.207mmol) was dissolved in DMF-DMA/EtOH (0.5 mL/0.5 mL) and the reactionmixture was heated to about 80° C. for 16 hours before it was cooled toroom temperature, and then concentrated under reduced pressure. Theresidue was used in the next step without further purification.

Step 6

Methyl8-((dimethylamino)methylene)-7-oxo-5,6,7,8-tetrahydroindolizine-2-carboxylate(15 mg) was dissolved in EtOH (0.5 mL) and methylhydrazine (0.1 mL) wasadded. The reaction mixture was refluxed for 2 hours before it wascooled to room temperature and concentrated under reduced pressure. Theresidue was purified with silica gel chromatography to afford methyl2-methyl-4,5-dihydro-2H-pyrazolo[3,4-g]indolizine-8-carboxylate andmethyl 3-methyl-4,5-dihydro-3H-pyrazolo[3,4-g]indolizine-8-carboxylate.

Step 7

Methyl 2-methyl-4,5-dihydro-2H-pyrazolo[3,4-g]indolizine-8-carboxylateand methyl3-methyl-4,5-dihydro-3H-pyrazolo[3,4-g]indolizine-8-carboxylate (10 mg)were dissolved in 1:1 mixture of dioxane/1 N NaOH. The reaction mixturewas heated to 80° C. for 1 hour before it was cooled to roomtemperature. The reaction mixture was washed with 1 N HCl and dilutedwith EtOAc. The organic layer was separated, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue was usedin the next step without further purification.

Step 8

The mixture of regio-isomers, methyl2-methyl-4,5-dihydro-2H-pyrazolo[3,4-g]indolizine-8-carboxylate andmethyl 3-methyl-4,5-dihydro-3H-pyrazolo[3,4-g]indolizine-8-carboxylatewere coupled to Example 109 in the same manner as Example 18 andseparated by reverse phase chromatography to give Example 208 andExample 209 respectively. The regio-chemistry is tentatively assigned.LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₃H₄₉ClN₆O₅S: 797.3; found: 797.0.

Example 210

Example 210 was synthesized in the same manner as Example 75 usingcis-3-(methoxymethyl)cyclobutan-1-amine hydrochloric acid and Example109. ¹H NMR (400 MHz, Acetone-d₆) δ 7.69 (d, J=8.6 Hz, 1H), 7.23 (br,1H), 7.09 (br, 3H), 6.87 (d, J=8.0 Hz, 1H), 6.07 (m, 1H), 5.63 (dd,J=15.4, 8.4 Hz, 1H), 4.23-3.96 (m, 4H), 3.88-3.79 (m, 2H), 3.71 (t,J=11.3 Hz, 2H), 3.41 (d, J=13.0 Hz, 1H), 3.31 (d, J=6.0 Hz, 2H), 3.26(s, 3H), 3.24 (s, 3H), 3.13 (dd, J=15.2, 10.1 Hz, 1H), 2.90-2.67 (m,3H), 2.61-2.07 (m, 9H), 2.01-1.66 (m, 6H), 1.42 (s, 1H), 1.13 (d, J=6.4Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₅₂ClN₄O₆S: 739.32; found:738.87.

Example 211

Example 211 was synthesized in the same manner as Example 75 using3-(methoxymethyl)bicyclo[1.1.1]pentan-1-amine hydrochloric acid andExample 109. ¹H NMR (400 MHz, Acetone-d₆) δ 7.66 (d, J=8.5 Hz, 1H),7.33-7.17 (m, 2H), 7.05 (d, J=22.1 Hz, 2H), 6.87 (d, J=8.2 Hz, 1H), 6.06(s, 1H), 5.66 (dd, J=15.5, 8.5 Hz, 1H), 4.18-3.92 (m, 3H), 3.89-3.62 (m,3H), 3.44 (s, 2H), 3.42 (d, J=10.2 Hz, 1H), 3.29 (s, 3H), 3.25 (s, 3H),3.13 (dd, J=15.2, 10.2 Hz, 1H), 2.79-2.06 (m, 11H), 1.99 (s, 6H),1.97-1.67 (m, 3H), 1.48-1.33 (m, 1H), 1.14 (d, J=6.5 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcd for C₄₀H₅₂ClN₄O₆S: 751.32; found: 750.72.

Example 212

Step 1: Preparation of Ethyl1-methyl-3-(methylamino)-1H-pyrazole-4-carboxylate

A roundbottom flask was charged with ethyl3-amino-1-methyl-pyrazole-4-carboxylate (267 mg, 1.58 mmol). The flaskwas placed under high vacuum for 5 min then backfilled with nitrogenatmosphere. THF (8 mL, 0.2 M limiting reagent) was added, followed bysodium hydride (60% dispersion in mineral oil, 73 mg, 1.89 mmol) at 20°C. The reaction mixture was stirred at 20° C. for 45 min, and theniodomethane (0.20 mL, 3.1 mmol) was added. The reaction was stirred at20° C. for 19 hr. More iodomethane (0.10 mL, 1.6 mmol) was added. Areflux condenser was installed under nitrogen atmosphere and thereaction was warmed to 70° C. in a metal heating block for 2 hr. Thereaction was monitored by LCMS until formation of both ethyl1-methyl-3-(methylamino)-1H-pyrazole-4-carboxylate and ethyl3-(dimethylamino)-1-methyl-1H-pyrazole-4-carboxylate were observed. Thereaction was removed from the heating block and allowed to cool to 20°C. The reaction was quenched with water and extracted into ethylacetate. The combined organic phases were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingresidue was dissolved in dichloromethane and purified by flash columnchromatography (silica gel, 24 g, 0 to 100% ethyl acetate in hexanes).The first UV-active product was eluted at 40% ethyl acetate, the secondUV-active product was eluted at 50% ethyl acetate, and the thirdUV-active product was eluted at 70% ethyl acetate. Fractions containingthe second UV-active product were collected and concentrated in vacuo toobtain ethyl 1-methyl-3-(methylamino)-1H-pyrazole-4-carboxylate (135mg). 1H NMR (400 MHz, Chloroform-d) δ 7.53 (s, 1H), 4.22 (q, J=7.1 Hz,2H), 3.72 (s, 3H), 2.93 (s, 3H), 1.29 (t, J=7.1 Hz, 3H).

Step 2: Preparation of 1-methyl-3-(methylamino)-1H-pyrazole-4-carboxylicAcid

To a glass screwtop vial charged with ethyl1-methyl-3-(methylamino)-1H-pyrazole-4-carboxylate (135 mg, 0.74 mmol)was added THF (7 mL), then methanol (3.5 mL), then sodium hydroxide (2 Min water, 1.8 mL, 3.6 mmol). The resulting mixture was stirredvigorously at 20° C. for 16 hr. The reaction was diluted with ethylacetate, and washed with water, then brine. The organic phase was driedover magnesium sulfate, filtered, and concentrated in vacuo. Theresulting crude product was dissolved in THF (3.8 mL), then sodiumhydroxide (2 M in water, 0.96 mL, 1.92 mmol) was added. The resultingmixture was stirred vigorously at 20° C. for 21 hr. More sodiumhydroxide (2 M in water, 0.96 mL, 1.92 mmol) was added, followed bymethanol (0.1 mL). The reaction was warmed to 60° C. in a metal heatingblock for 4 hr. The reaction was monitored by silica gel TLC (1:1hexanes:ethyl acetate) until complete consumption of starting ester wasobserved. The vial was removed from the heating block and allowed tocool to 20° C. The reaction was quenched with 2 N HCl, which was addeddropwise until pH<3 by pH paper. The resulting mixture was extractedthree times with ethyl acetate. The combined organic phases were driedover magnesium sulfate, filtered, and concentrated in vacuo. NMR wasconsistent with 1-methyl-3-(methylamino)-1H-pyrazole-4-carboxylic acid,in at least 95% purity (50 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.76 (s,1H), 3.71 (s, 3H), 2.87 (s, 3H).

Step 3

Example 212 was synthesized in the same manner as Example 18 using1-methyl-3-(methylamino)-1H-pyrazole-4-carboxylic acid and Example 109.1H NMR (400 MHz, Acetonitrile-d3) δ 8.18 (s, 1H), 7.54 (d, J=8.6 Hz,1H), 7.18 (d, J=8.2 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.97-6.84 (m, 2H),6.80 (d, J=8.2 Hz, 1H), 6.04-5.93 (m, 1H), 5.61 (dd, J=15.3, 8.6 Hz,1H), 4.24-4.08 (m, 1H), 3.95 (d, J=3.0 Hz, 2H), 3.81-3.65 (m, 2H), 3.74(s, 3H), 3.59 (d, J=14.4 Hz, 1H), 3.36 (d, J=14.4 Hz, 1H), 3.21 (s, 3H),3.07 (dd, J=15.4, 10.4 Hz, 1H), 2.89 (s, 3H), 2.83-2.57 (m, 3H),2.48-2.33 (m, 2H), 2.29-2.05 (m, 3H), 2.05-1.97 (m, 1H), 1.92-1.66 (m,7H), 1.33 (dd, J=14.6, 8.2 Hz, 1H), 1.08 (d, J=6.3 Hz, 3H). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₃₈H₄₇ClN₆O₅S: 735.31; found: 735.05.

Example 213

Step 1: Preparation of Ethyl3-(dimethylamino)-1-methyl-1H-pyrazole-4-carboxylate

A roundbottom flask was charged with ethyl3-amino-1-methyl-pyrazole-4-carboxylate (267 mg, 1.58 mmol). The flaskwas placed under high vacuum for 5 min, then backfilled with nitrogenatmosphere. THF (8 mL, 0.2 M limiting reagent) was added, followed bysodium hydride (60% dispersion in mineral oil, 73 mg, 1.89 mmol) at 20°C. The flask was stirred at 20° C. for 45 min, then iodomethane (0.20mL, 3.1 mmol) was added. The reaction was stirred at 20° C. for 19 hr.More iodomethane (0.10 mL, 1.6 mmol) was added. A reflux condenser wasinstalled under nitrogen atmosphere and the reaction was warmed to 70°C. in a metal heating block for 2 hr. The reaction was monitored by LCMSuntil formation of both ethyl1-methyl-3-(methylamino)-1H-pyrazole-4-carboxylate and ethyl3-(dimethylamino)-1-methyl-1H-pyrazole-4-carboxylate were observed. Thereaction was removed from the heating block and allowed to cool to 20°C. The reaction was quenched with water and extracted into ethylacetate. The combined organic phases were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingresidue was dissolved in dichloromethane and purified by flash columnchromatography (silica gel, 24 g, 0 to 100% ethyl acetate in hexanes).The first UV-active product was eluted at 40% ethyl acetate, the secondUV-active product was eluted at 50% ethyl acetate, and the thirdUV-active product was eluted at 70% ethyl acetate. Fractions containingprimarily the first UV-active product were collected and concentrated invacuo to obtain ethyl3-(dimethylamino)-1-methyl-1H-pyrazole-4-carboxylate (35 mg). 1H NMR(400 MHz, Chloroform-d) δ 7.69 (s, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.72 (s,3H), 2.89 (s, 6H), 1.29 (t, J=7.1 Hz, 3H).

Step 2: Preparation of3-(dimethylamino)-1-methyl-1H-pyrazole-4-carboxylic Acid

To a glass screwtop vial charged with starting material was added THF,then methanol, then sodium hydroxide (2 M in water). The resultingmixture was stirred vigorously at 20° C. for 16 hr. The reaction wasquenched by careful addition of 2 N aqueous HCl until pH<3 by pH paper.The mixture was extracted with ethyl acetate, and washed with water,then brine. The organic phase was dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting residue wasre-dissolved in THF (1.4 mL), then sodium hydroxide (2 M in water, 0.34mL) was added. The resulting mixture was stirred vigorously at 20° C.for 18 hr. Then more sodium hydroxide (2 M in water, 0.34 mL) was added,followed by methanol (100 μL). The reaction was warmed to 60° C. in ametal heating block for 12 hr. The reaction was monitored by silica gelTLC (1:1 hexanes:ethyl acetate) until all starting material wasconsumed. The reaction was quenched with 2 N HCl, which was addeddropwise until pH<3 by pH paper. The resulting mixture was extractedthree times with ethyl acetate. The combined organic phases were driedover magnesium sulfate, filtered, and concentrated in vacuo to give3-(dimethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid (20 mg), whichwas used in the next step without any further purification. 1H NMR (400MHz, Methanol-d4) δ 7.93 (s, 1H), 3.74 (s, 3H), 2.86 (s, 6H).

Step 3

Example 213 was synthesized in the same manner as Example 18 using3-(dimethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid and Example109. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.04 (s, 1H), 7.70 (d, J=8.5Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 7.08 (dd,J=8.2, 1.9 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 5.90(dt, J=14.2, 6.7 Hz, 1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 4.41 (dd,J=15.0, 6.3 Hz, 1H), 4.05 (s, 2H), 3.88 (s, 3H), 3.79 (dd, J=15.0, 4.0Hz, 2H), 3.72-3.59 (m, 2H), 3.24 (s, 6H), 3.17 (s, 3H), 3.06 (dd,J=15.3, 10.5 Hz, 1H), 2.84-2.65 (m, 2H), 2.51-2.31 (m, 2H), 2.25 (t,J=8.6 Hz, 1H), 2.19-2.10 (m, 1H), 2.05 (d, J=13.8 Hz, 2H), 1.89 (d,J=7.1 Hz, 4H), 1.81-1.61 (m, 4H), 1.46-1.35 (m, 1H), 1.07 (d, J=6.7 Hz,3H). LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₃₉H₄₉ClN₆O₅S: 749.32;found: 749.18.

Example 214

Example 214 was synthesized in a manner similar to Example 167 using(R)-2-(methoxymethyl)oxirane instead of (S)-2-methyloxirane and Example109. 1H NMR (400 MHz, Acetone-d6) δ 7.78 (d, J=8.5 Hz, 1H), 7.48 (s,1H), 7.34 (d, J=8.2 Hz, 1H), 7.29-7.20 (m, 2H), 7.14 (d, J=2.3 Hz, 1H),6.92 (d, J=8.2 Hz, 1H), 6.33 (s, 1H), 6.26-6.00 (m, 1H), 5.70-5.56 (m,1H), 4.95 (d, J=14.4 Hz, 1H), 4.74 (d, J=14.4 Hz, 1H), 4.26-3.68 (m,9H), 3.64 (dd, J=10.4, 5.4 Hz, 1H), 3.55 (dd, J=10.4, 4.8 Hz, 1H), 3.44(d, J=14.3 Hz, 1H), 3.39 (s, 3H), 3.25 (s, 3H), 3.15 (dd, J=15.2, 10.3Hz, 1H), 2.90-1.40 (m, 16H), 1.14 (d, J=6.4 Hz, 3H). LCMS: 813.2(M+Na)+.

Example 215

Example 215 was synthesized in a manner similar to Example 214 usingExample 110 instead of 109. 1H NMR (400 MHz, Acetone-d6) δ 7.78 (d,J=8.5 Hz, 1H), 7.51-7.19 (m, 4H), 7.14 (s, 1H), 7.05-6.92 (m, 1H),6.34-6.21 (m, 1H), 6.09-5.95 (m, 1H), 5.63-5.53 (m, 1H), 4.91 (d, J=14.3Hz, 1H), 4.72 (d, J=14.4 Hz, 1H), 4.64-3.60 (m, 10H), 3.54 (dd, J=10.5,4.9 Hz, 1H), 3.46-3.11 (m, 2H), 3.39 (s, 3H), 3.19 (s, 3H), 2.93-0.81(m, 21H). LCMS: 827.1 (M+Na)+.

Example 216

Step 1

3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.704 mmol)was dissolved in DMF (3 mL) and sodium hydride (60% dispersion, 84 mg,2.1 mmol, 3 equiv.) was added in one portion. 1-Iodo-2-m ethoxy ethane(2.1 mmol, 391 mg, 3 equiv.) was added via pipette. The reaction mixturewas heated to 80° C. until TLC indicated the complete consumption ofstarting material. The reaction mixture was quenched with saturatedNH₄Cl (3 mL), then diluted with EtOAc (10 mL). The organic layer waswashed with saturated NaHCO₃ (10 mL) and brine (10 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified via column chromatography to afford2-methoxy ethyl 3-(2-m ethoxyethoxy)-1-methyl-1H-pyrazole-4-carboxylate.

Step 2

2-methoxyethyl 3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-4-carboxylate(20 mg, 0.08 mmol) was dissolved in a 1:1 mixture of 1,2-dioxane (1 mL)and 1 N NaOH solution (1 mL). The reaction mixture was heated to 80° C.for 4 hours (reaction monitored by TLC and LCMS). The reaction mixturewas then cooled to room temperature and quenched with 1 M HCl (1.5 mL)then diluted with EtOAc (5 mL). The organic layer was washed withsaturated NaHCO₃ (5 mL) and brine (5 mL). The organic layer was driedover Na₂SO₄, filtered, and concentrated under reduced pressure to afford3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-4-carboxylic acid which wasused without further purification.

Step 3

Example 216 was synthesized in the same manner as Example 18 using3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-4-carboxylic acid and Example109. LCMS-ESI+(m/z): [M+H]+ calcd for C₄₀H₄₉ClN₅O₇S: 780.3; found:780.0.

Example 217

Example 217 was synthesized in the same manner as Example 75 using2-oxaspiro[3.3]heptan-6-amine hydrochloric acid and Example 109. ¹H NMR(400 MHz, Acetone-d₆) δ 7.59 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H),7.05 (d, J=3.8 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 6.08 (d, J=13.1 Hz, 1H),5.73 (d, J=12.7 Hz, 1H), 4.65 (s, 2H), 4.55-4.47 (AB q, 2H), 4.17-4.01(m, 2H), 3.86-3.70 (m, 2H), 3.66 (d, J=14.3 Hz, 1H), 3.46 (d, J=14.4 Hz,1H), 3.27 (s, 3H), 3.20-3.07 (m, 1H), 3.03-2.08 (m, 12H), 2.02-1.67 (m,3H), 1.15 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₉H₅₀ClN₄O₆S: 737.31; found: 737.05.

Example 218

Example 218 was synthesized in a manner similar to Example 167 usingExample 110 instead of Example 109. 1H NMR (400 MHz, Acetone-d6) δ 7.78(d, J=8.5 Hz, 1H), 7.39 (d, J=1.7 Hz, 1H), 7.28-7.24 (m, 1H), 7.24-7.20(m, 1H), 7.17-7.07 (m, 2H), 7.01 (d, J=8.1 Hz, 1H), 6.29 (d, J=1.5 Hz,1H), 6.04-5.95 (m, 1H), 5.57 (dd, J=15.3, 8.7 Hz, 1H), 4.89 (dd, J=14.3,0.9 Hz, 1H), 4.71 (dd, J=14.4, 1.3 Hz, 1H), 4.54-4.38 (m, 1H), 4.19-4.06(m, 3H), 4.04-3.92 (m, 1H), 3.92-3.81 (m, 1H), 3.79-3.60 (m, 3H), 3.39(d, J=14.2 Hz, 1H), 3.26-3.11 (m, 1H), 3.17 (s, 3H), 2.91-1.67 (m, 15H),1.58 (d, J=7.1 Hz, 3H), 1.54-1.41 (m, 1H), 1.32 (d, J=6.1 Hz, 3H), 1.05(d, J=6.8 Hz, 3H). LCMS: 775.0.

Example 219

Example 219 was synthesized in the same manner as Example 18, usingExample 109 instead of Example 5 and2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylic acid was used instead of3-methoxypropionic acid. 1H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J=8.5Hz, 1H), 7.26 (dd, J=8.3, 1.8 Hz, 1H), 7.19 (dd, J=8.5, 2.3 Hz, 1H),7.12 (d, J=2.3 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.07 (dt,J=14.2, 6.8 Hz, 1H), 5.96 (s, 1H), 5.62 (dd, J=15.3, 8.7 Hz, 1H), 5.16(t, J=8.1 Hz, 2H), 4.49-4.37 (m, 2H), 4.29 (dd, J=15.0, 6.3 Hz, 2H),4.15-3.94 (m, 3H), 3.87 (d, J=15.0 Hz, 1H), 3.83-3.75 (m, 1H), 3.71 (d,J=14.3 Hz, 1H), 3.29 (s, 3H), 3.09 (dd, J=15.3, 9.6 Hz, 2H), 2.90-2.71(m, 3H), 2.47 (s, 3H), 2.33-2.07 (m, 3H), 2.05-1.88 (m, 3H), 1.81 (dd,J=21.4, 8.9 Hz, 3H), 1.46 (t, J=11.8 Hz, 1H), 1.13 (d, J=6.6 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₄ClN₅O₆S: 734.27; found: 733.75.

Example 220

Example 220 was synthesized in the same manner as Example 18 usingintermediate 201-1 and 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid.¹H NMR (400 MHz, Methanol-d4) δ 7.98 (s, 1H), 7.79 (d, J=8.6 Hz, 1H),7.25 (s, 1H), 7.19 (d, J=9.1 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 6.99 (s,1H), 6.85 (d, J=8.3 Hz, 1H), 6.17 (s, 1H), 5.52 (s, 1H), 4.10-3.99 (m,2H), 3.95 (d, J=3.3 Hz, 2H), 3.89 (d, J=15.1 Hz, 1H), 3.84-3.79 (m, 1),3.77 (s, 3H), 3.68 (d, J=14.2 Hz, 1H), 3.26 (s, 4H), 3.07-2.89 (m, 1H),2.89-2.73 (m, 2H), 2.69 (d, J=17.0 Hz, 1H), 2.43 (s, 2H), 2.13 (m, 3H),1.97 (m, 3H), 1.76 (d, J=9.2 Hz, 3H), 1.53-1.32 (m, 4), 0.93 (t, J=7.3Hz, 3H). LCMS-ESI+: calc'd for C₃₉H₄₉ClN₅O₆S: 750.30 (M+H); found:750.80 (M+H).

Example 221

Step 1

3-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.704 mmol)was dissolved in DMF (3 mL) and sodium hydride (60% dispersion, 84 mg,2.1 mmol, 3 equiv.) was added in one portion. (Iodomethyl)cyclopropane(2.1 mmol, 382 mg, 3 equiv.) was added via pipette. The reaction mixturewas heated to 80° C. until TLC indicated the complete consumption ofstarting material. The reaction mixture was quenched with saturatedNH₄Cl (3 mL), then diluted with EtOAc (10 mL). The organic layer waswashed with saturated NaHCO₃ (10 mL) and brine (10 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified via column chromatography to affordcyclopropylmethyl3-(cyclopropylmethoxy)-1-methyl-1H-pyrazole-4-carboxylate.

Step 2

Cyclopropylmethyl3-(cyclopropylmethoxy)-1-methyl-1H-pyrazole-4-carboxylate (20 mg, 0.08mmol) was dissolved in a 1:1 mixture of 1,2-dioxane (1 mL) and 1 N NaOHsolution (1 mL). The reaction mixture was heated to 80° C. for 4 hours(reaction was monitored by TLC and LCMS). The reaction mixture was thencooled to room temperature, quenched with 1 M HCl (1.5 mL), then dilutedwith EtOAc (5 mL). The organic layer was washed with saturated NaHCO₃ (5mL) and brine (5 mL). The organic layer was dried over Na₂SO₄, filtered,and concentrated under reduced pressure to afford3-(cyclopropylmethoxy)-1-methyl-1H-pyrazole-4-carboxylic acid that wasused without further purification.

Step 3

Example 221 was synthesized in the same manner as Example 18 using3-(cyclopropylmethoxy)-1-methyl-1H-pyrazole-4-carboxylic acid andExample 109. LCMS-ESI+(m/z) [M+H]+: calcd for C₄₁H₅₀ClN₅O₆S: 776.3,found: 776.0.

Example 222

Example 222 was prepared in a similar manner to Example 75 using(1R,3R)-3-aminocyclopentan-1-ol, triethylamine and Example 109. 1H NMR(400 MHz, DMSO-d6) δ 7.63 (d, J=8.5 Hz, 1H), 7.24 (dd, J=8.5, 2.3 Hz,1H), 7.18-7.08 (m, 2H), 6.96 (s, 1H), 6.86 (d, J=8.0 Hz, 2H), 6.06-5.86(m, 1H), 5.47 (dd, J=15.3, 8.7 Hz, 1H), 4.20-3.97 (m, 4H), 3.92 (d,J=12.2 Hz, 1H), 3.84 (d, J=13.7 Hz, 1H), 3.73 (d, J=14.8 Hz, 1H),3.66-3.48 (m, 2H), 3.31 (s, 6H), 3.20 (d, J=14.2 Hz, 1H), 3.12 (s, 3H),3.05-2.92 (m, 1H), 2.86-2.58 (m, 3H), 2.43-2.17 (m, 2H), 2.15-1.55 (m,8H), 1.55-1.24 (m, 2H), 0.98 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₈H₄₉ClN₄O₆S: 725.31; found: 724.82.

Example 223

Step 1

To a stirred solution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (1140 mg, 2.4 mmol) in DCM(100 mL) was added 109-2-2 (703 mg, 2.55 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (756 mg, 4.87 mmol)and 4-(dimethylamino)pyridine (595 mg, 4.87 mmol). The reaction mixturewas stirred at room temperature for 4 hr. Then the reaction mixture wasdiluted with DCM, washed with 1 N HCl and brine. The organic phase wasdried over MgSO₄, filtered, and concentrated to give intermediate 223-1.

Step 2

To a stirred solution of 223-1 (1300 mg, 1.83 mmol) in methanol (50 mL)was added water (5 mL), K₂CO₃ (899 mg, 9.17 mmol), and the reactionmixture was stirred at 60° C. for 24 hrs. More water was added and themixture was extracted with dichloromethane. The organic phase was driedover anhydrous magnesium sulfate and the solvent was removed underreduced pressure down to yield 223-2.

Step 3

To a stirred solution of 223-2 (1000 mg, 1.63 mmol) in DCM (25 mL) wasadded 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (280 mg, 1.79mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (507 mg, 3.26mmol) and 4-(dimethylamino)pyridine (399 mg, 3.26 mmol). The reactionmixture was stirred at room temperature for 24 h. Then the reactionmixture was diluted with DCM, and washed with 1 N HCl and brine. Theorganic phase was dried over MgSO₄, filtered, concentrated, and purifiedon normal phase chromatography 0-10% DCM/MeOH to yield 223-3.

Step 4

To a stirred solution of 223-3 (1000 mg, 1.33 mmol), Hoveyda-Grubbs II(339 mg, 0.40 mmol) and TFA (455 mg, 3.99 mmol) in 1,2-dichloroethane(370 mL) was degassed with argon. The reaction mixture was stirred at80° C. for 1 hr. The reaction mixture was concentrated and purified onreversed phase chromatography 0.1% TFA 70-95% acetonitrile to giveExample 223. 1H NMR (400 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.77 (d,J=8.5 Hz, 1H), 7.50 (dd, J=8.2, 1.9 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H),7.20 (dd, J=8.5, 2.4 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.2 Hz,1H), 5.64 (t, J=7.3 Hz, 2H), 4.74-4.64 (m, 1H), 4.21-4.01 (m, 4H), 3.96(d, J=15.1 Hz, 1H), 3.86-3.63 (m, 4H), 3.35 (d, J=14.4 Hz, 1H), 3.16(dd, J=15.3, 9.1 Hz, 1H), 2.79 (dd, J=10.0, 5.3 Hz, 2H), 2.67-2.48 (m,2H), 2.45-2.21 (m, 5H), 1.46 (td, J=14.8, 6.9 Hz, 2H), 1.28 (s, 4H),1.13 (d, J=7.1 Hz, 4H), 0.96-0.77 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₃₇H₄₄ClN₅O₆S: 722.27; found: 722.33.

Example 224

Step 1

To a stirred solution of (2S,4R)-4-methoxypyrrolidine-2-carboxylic acid(1.5 g, 10.33 mmol), DIPEA (5.4 mL, 31.0 mmol) in THF (48 mL) and EtOH(32 mL) was added ethyl propiolate (1.0 g, 10.33 mmol) over 2 min atroom temperature. The reaction was stirred at room temperature for 2hours, and then concentrated under reduced pressure. Solids weredissolved with 150 mL of DCM and then DMAP (0.63 g, 5.2 mmol), DIPEA(3.9 mL, 22.7 mmol) and triphenyl phosphine (3.1 g, 12.0 mmol) wereadded. The mixture was cooled down to 0° C. and iodine (3.0 g, 11.9mmol) was added. The mixture was stirred vigorously over 40 min to reachroom temperature and then heated at 50° C. for 1 hr. DCM, 0.2M HCl, andbrine were added, organic phase was extracted, dried over Mg₂SO₄, andconcentrated under reduced pressure. The resulting residue was dissolvedin acetone (60 mL) and combined with Cs₂CO₃ (13.5 g, 41.3 mmol) andmethyl sulfate (6.5 g, 51.7 mmol), stirred at room temperature for 60min. Solids were filtered out and organic layers were purified on normalphase chromatography (0 to 35% EtOAc/hexanes) to yield 224-1.

Step 2

To a stirred solution of 224-1 (120 mg, 0.53 mmol) in methanol (3 mL)was added THF (3 mL) and 2 N of NaOH (1 mL) and stirred at roomtemperature for 48 h. To the reaction mixture was added 2 N HCl (1 mL)and the reaction mixture was concentrated. Water was added and themixture was extracted with dichloromethane. The organic phase was driedover anhydrous magnesium sulfate and the solvent was removed underreduced pressure to give 224-2.

Step 3

Example 224 was synthesized in the same manner as Example 174 (step 3)using (R)-2,7-dimethoxy-2,3-dihydro-1H-pyrrolizine-6-carboxylic acid andExample 109. 1H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.5 Hz, 1H),7.48 (dd, J=8.2, 1.8 Hz, 1H), 7.24-7.15 (m, 3H), 7.10 (d, J=2.3 Hz, 1H),6.93 (d, J=8.3 Hz, 1H), 6.11 (dt, J=14.0, 6.6 Hz, 1H), 5.60 (dd, J=15.6,7.8 Hz, 1H), 4.53 (tt, J=6.2, 3.5 Hz, 1H), 4.22-3.92 (m, 6H), 3.91-3.68(m, 3H), 3.43 (m, 3H), 3.37-3.22 (m, 6H), 3.18-2.92 (m, 3H), 2.90-2.70(m, 2H), 2.66-2.27 (m, 4H), 2.23-1.61 (m, 6H), 1.28 (m, 4H), 1.11 (d,J=6.8 Hz, 3H), 0.96-0.72 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₂H₅₁ClN₄O₇S: 791.32; found: 791.35.

Example 225

Step 1

Synthesis of 225-1: cis-3-Amino-1-methyl-cyclobutanol HCl salt (340 mg,3.36 mmol) was treated with DCM (3.0 mL) and DMF (1.5 mL) at roomtemperature. DIEA (1.303 g, 10.1 mmol) was added followed bydi-tert-butyl dicarbonate (880 mg, 4.03 mmol). The resulting mixture wasstirred at rt for 4 hrs. The reaction was then diluted with EtOAc (15.0mL), washed with 1 N HCl (3.0 mL), sat. NaHCO₃ (3.0 mL), brine (3.0 mL),dried over sodium sulfate, filtered, and concentrated to give crude225-1 for using directly.

Step 2

Synthesis of 225-2: 225-1 (147 mg, 0.73 mmol) in a mixture of THF (1.5mL) and DMF (1.5 mL) was cooled to 0° C., NaH (60 wt % dispersion inmineral oil, 42 mg, 1.10 mmol) was added. After stirred for 20 min, EtI(137 mg, 0.876 mmol) was added. The reaction was slowly warmed up to rtand stirred at room temperature for 3 hrs. The reaction was thenpartitioned between EtOAc (15.0 mL) and water (3.0 mL). The organiclayer was washed with brine (3.0 mL), dried over sodium sulfate,filtered, and concentrated to give crude product, which was purified bycombiflash (4 g silica gel, 0-43% EtOAc/Hexanes). The 2nd eluted peakwas the desired product. 1H NMR (400 MHz, Chloroform-d) δ 4.71-4.61 (m,1H), 3.90-3.80 (m, 1H), 3.35 (q, J=7.0 Hz, 2H), 2.44-2.35 (m, 2H),1.97-1.88 (m, 2H), 1.45 (s, 9H), 1.32 (d, J=0.9 Hz, 3H), 1.19 (t, J=7.0Hz, 3H).

Step 3: Preparation of 225-3

225-2 from previous step was dissolved in DCM (2.4 mL) at roomtemperature, 4 N HCl in 1,4-dioxane (0.8 mL) was added dropwise. Thereaction was stirred at rt for 1 hr. The reaction was concentrated, andco-evaporated with EtOAc (3×) to give 225-3.

Step 4

Example 225 was synthesized in the same manner as Example 75 withExample 109 and 225-3 and DIEA. 1H NMR (400 MHz, Methanol-d4) δ 7.69 (d,J=8.5 Hz, 1H), 7.24-7.17 (m, 1H), 7.11-7.05 (m, 2H), 6.99 (s, 1H), 6.88(d, J=8.1 Hz, 1H), 6.10-5.99 (m, 1H), 5.62 (dd, J=15.4, 8.9 Hz, 1H),4.23 (dd, J=14.8, 7.0 Hz, 1H), 4.07-4.00 (m, 2H), 3.96-3.86 (m, 1H),3.86-3.74 (m, 3H), 3.66 (d, J=14.3 Hz, 1H), 3.42 (q, J=7.0 Hz, 2H), 3.29(s, 3H), 3.12-3.02 (m, 1H), 2.89-2.73 (m, 2H), 2.57-2.31 (m, 6H),2.28-2.02 (m, 7H), 1.86-1.73 (m, 4H), 1.41 (t, J=11.0 Hz, 1H), 1.31 (s,3H), 1.19 (t, J=7.0 Hz, 3H), 1.14 (d, J=6.7 Hz, 3H). [M+H]+ calcd forC₄₀H₅₃ClN₄O₆S: 753.39; found: 752.79.

Example 226

Example 226 was synthesized in the same manner as Example 75 usingtrans-3-aminocyclobutyl diethylcarbamate tetrakis-trifluoroacetic acidand Example 109. 1H NMR (400 MHz, Methanol-d4) δ 7.72 (d, J=8.5 Hz, 1H),7.16 (d, J=8.8 Hz, 1H), 7.09 (d, J=5.7 Hz, 2H), 6.95-6.86 (m, 2H), 5.95(dt, J=14.3, 6.9 Hz, 1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 5.15-5.05 (m,1H), 4.45-4.22 (m, 3H), 4.15-3.89 (m, 4H), 3.83 (d, J=15.1 Hz, 1H), 3.74(dd, J=9.2, 3.6 Hz, 1H), 3.70-3.54 (m, 2H), 3.35 (m, 4H), 3.27 (d,J=14.8 Hz, 1H), 3.24 (s, 3H), 3.06 (dd, J=15.3, 10.3 Hz, 1H), 2.89-2.66(m, 2H), 2.54-2.39 (m, 2H), 2.33 (q, J=9.1 Hz, 1H), 2.24-2.03 (m, 3H),2.01-1.65 (m, 6H), 1.43 (t, J=13.4 Hz, 1H), 1.13 (d, J=6.6).

Example 227

Example 227 was synthesized in the same manner as Example 237 usingintermediate 375-2 and (1S,2R)-2-(difluoromethyl)cyclopropan-1-aminehydrochloride. ¹H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H),7.24-7.14 (m, 2H), 7.12 (d, J=2.3 Hz, 1H), 7.00 (s, 1H), 6.91 (d, J=8.2Hz, 1H), 6.02-5.91 (m, 1H), 5.86-5.66 (m, 2H), 4.23 (dd, J=15.1, 3.3 Hz,1H), 4.08 (s, 2H), 3.95-3.76 (m, 2H), 3.72 (d, J=8.1 Hz, 1H), 3.67 (d,J=14.3 Hz, 1H), 3.31 (d, J=1.2 Hz, 7H), 3.15-3.05 (m, 1H), 2.92-2.69 (m,3H), 2.54 (d, J=9.7 Hz, 1H), 2.46-2.29 (m, 1H), 2.17-2.00 (m, 2H),2.00-1.91 (m, 2H), 1.91-1.68 (m, 2H), 1.54 (m, 1H), 1.45 (t, J=13.2 Hz,1H), 1.31 (s, 1H), 1.25 (d, J=6.8 Hz, 3H), 1.10 (q, J=6.6 Hz, 1H), 0.93(m, 2H). LCMS-ESI+: calc'd for C₃₈H₄₈ClF₂N₄O₆S: 761.29 (M+H); found:761.26 (M+H).

Example 228

Preparation of Intermediate 228-1: A stirred mixture of 106-2 (2.14 g,3.42 mmol), magnesium oxide (413 mg, 10.3 mmol), and(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium(449 mg, 717 μmol) in 1,2-dichloroethane (485 mL) was heated 80° C.After 18.5 h, the resulting mixture was cooled to room temperature,filtered through celite, and concentrated under reduced pressure. Theresidue was dissolved in a mixture of ethyl acetate (50 mL) and toluene(100 mL). Silica gel (40 g) was added, and the resulting slurry wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (0 to 65% ethyl acetate in hexanes)to give a mixture of intermediate 106-4 and Intermediate 228-1. Themixture was purified by reverse phase preparative hplc (0.1%trifluoroacetic acid in acetonitrile/water) to give Intermediate 228-1.1H NMR (400 MHz, Acetone-d6) δ 7.79 (d, J=8.5 Hz, 1H), 7.39 (d, J=1.9Hz, 1H), 7.31 (dd, J=8.2, 1.9 Hz, 1H), 7.24 (dd, J=8.5, 2.4 Hz, 1H),7.14 (d, J=2.3 Hz, 1H), 7.07 (s, 1H), 6.89 (d, J=8.2 Hz, 1H), 5.82 (td,J=9.8, 6.1 Hz, 1H), 5.54-5.43 (m, 1H), 4.28-4.17 (m, 1H), 4.11 (d,J=12.1 Hz, 1H), 4.01 (d, J=12.1 Hz, 1H), 3.94 (d, J=15.1 Hz, 1H), 3.78(d, J=14.3 Hz, 1H), 3.64 (dd, J=14.3, 3.4 Hz, 1H), 3.49 (d, J=14.3 Hz,1H), 3.40 (dd, J=14.3, 8.1 Hz, 1H), 3.28 (dd, J=15.2, 10.7 Hz, 1H), 3.23(s, 3H), 2.88-1.27 (m, 15H), 1.17 (d, J=6.9 Hz, 3H). LCMS: 598.2.

Example 228 was synthesized in the same manner as Example 18 usingIntermediate 228-land 3-methoxy-1-methyl-pyrazole-4-carboxylic acid. 1HNMR (400 MHz, Methanol-d4) δ 8.14 (s, 1H), 7.78-7.68 (m, 1H), 7.37 (dd,J=8.2, 1.9 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.16-7.09 (m, 2H), 6.91 (d,J=8.2 Hz, 1H), 5.88-5.76 (m, 1H), 5.55-5.45 (m, 1H), 4.31-4.24 (m, 1H),4.14-3.98 (m, 6H), 3.95-3.88 (m, 1H), 3.82 (s, 3H), 3.79-3.66 (m, 2H),3.48 (d, J=14.3 Hz, 1H), 3.30 (s, 3H), 3.27-3.19 (m, 1H), 2.97-2.72 (m,3H), 2.57-2.35 (m, 3H), 2.34-2.23 (m, 1H), 2.17-2.08 (m, 1H), 2.02-1.90(m, 3H), 1.89-1.79 (m, 3H), 1.53-1.42 (m, 1H), 1.14 (d, J=7.0 Hz, 3H).LCMS-ESI+ (m/z): calcd H+ for C₃₈H₄₆ClN₅O₆S: 736.29; found: 736.08.

Example 229

Step 1

A stirred mixture of methyl 5-formyl-1H-pyrrole-3-carboxylate (700 mg,4.57 mmol), (S)-4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (2.12 g, 8.76mmol), and potassium carbonate (1.58 g, 11.4 mmol) inN,N-dimethylformamide (18 mL) was heated to 85° C. After 16 h, theresulting mixture was cooled to room temperature, and diethyl ether (250mL), ethyl acetate (150 mL), and saturated aqueous ammonium chloridesolution (20 mL) were added sequentially. The organic layer was washedwith water (2×400 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (0 to 45% ethyl acetate inhexanes) to give 229-1.

Step 2

Aqueous hydrogen chloride solution (6.0 M, 2.87 mL, 17 mmol) was addedvia syringe to a stirred solution of 229-1 (766 mg, 2.87 mmol) inmethanol (11.5 mL) at room temperature. After 30 min, saturated aqueoussodium carbonate solution (9 mL), brine (30 mL), and water (20 mL) wereadded sequentially. The aqueous layer was extracted with dichloromethane(4×60 mL). The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was dissolved in dichloromethane (200 mL) and methanol (1.16mL), and the mixture was stirred at room temperature. Trifluoroaceticacid (2.19 mL, 28.7 mmol) was added via syringe. After 1 min,triethylsilane (4.81 mL, 30.1 mmol) was added via syringe. After 40 min,trifluoroacetic acid (4.38 mL, 57.4 mmol) and triethylsilane (9.6 mL,60.2 mmol) were added sequentially via syringe. After 30 min, saturatedaqueous sodium carbonate solution (43 mL) and brine (100 mL) were addedsequentially. The organic layer was separated, and the aqueous layer wasextracted with dichloromethane (100 mL). The combined organic layerswere dried over anhydrous magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 75% ethyl acetate in hexanes) to give229-2.

Step 3

Iodine (37.7 mg, 148 μmol) was added to a stirred mixture of 229-2 (15mg, 71 μmol), triphenylphosphine (38.9 mg, 148 μmol), and imidazole(14.5 mg, 213 μmol) in tetrahydrofuran (1.0 mL) at room temperature.After 50 min, (R)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride(153 mg, 710 μmol), potassium carbonate (294 mg, 2.13 mmol), andacetonitrile (1.0 mL) were added sequentially, and the resulting mixturewas heated to 60° C. After 135 min, the resulting mixture was cooled toroom temperature, and water (15 mL) and brine (15 mL) were addedsequentially. The aqueous layer was extracted sequentially withdichloromethane (30 mL) and ethyl acetate (30 mL). The combined organiclayers were dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (0 to 9% methanol indichloromethane) to give 229-3.

Step 4: Preparation of Example 229

Aqueous sodium hydroxide solution (2.0 M, 54 μL, 108 μmol) was added viasyringe to a stirred mixture of 229-3 (3.0 mg, 14 μmol) intetrahydrofuran (0.7 mL) and methanol (0.2 mL) at room temperature. Theresulting mixture was heated to 80° C. After 17.5 h, the resultingmixture was cooled to room temperature and was concentrated underreduced pressure. The residue was dried azeotropically by concentrationunder reduced pressure from toluene (2 mL). Tetrahydrofuran (2 mL) andhydrogen chloride solution (2.0 M in 1,4-dioxane, 27.2 μL) were addedsequentially, and the resulting mixture was concentrated under reducedpressure. The residue was dried azeotropically by concentration underreduced pressure from toluene (2 mL). Intermediate 359-4 (6.5 mg, 11μmol), 4-dimethylaminopyridine (4.0 mg, 33 μmol), trimethylamine (6.1μL, 43 μmol) and dichloromethane (1.0 mL) were added sequentially, andthe resulting mixture was stirred at room temperature.3-(((Ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (2.7 mg, 14 μmol) was added, and the resulting mixture washeated to 45° C. After 60 min, the resulting mixture was cooled to roomtemperature and was concentrated under reduced pressure. The residue waspurified by reverse phase preparative HPLC (0.1% trifluoroacetic acid inacetonitrile/water) to give Example 229. 1H NMR (400 MHz, Acetone-d6) δ7.78 (d, J=8.3 Hz, 1H), 7.42 (s, 1H), 7.31-7.17 (m, 3H), 7.15 (d, J=2.6Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.31 (s, 1H), 5.93-5.79 (m, 1H), 5.74(dd, J=15.3, 7.3 Hz, 1H), 4.93 (d, J=14.6 Hz, 1H), 4.79 (d, J=14.5 Hz,1H), 4.54-1.66 (m, 40H), 1.56 (d, J=7.1 Hz, 3H), 1.54-1.43 (m, 1H),1.10-0.98 (m, 3H). LCMS: 901.3.

Example 230

Example 230 was prepared in a similar manner to Example 75 using1-oxa-6-azaspiro[3.3]heptane, triethylamine and Example 109. ¹H NMR (400MHz, DMSO-d₆) δ 7.65 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5, 2.4 Hz, 1H),7.18 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.2, 1.8 Hz, 1H), 6.92 (d, J=8.1 Hz,1H), 6.85 (d, J=1.9 Hz, 1H), 5.88 (dt, J=14.3, 6.8 Hz, 1H), 5.49 (dd,J=15.2, 8.8 Hz, 1H), 4.40 (t, J=7.4 Hz, 2H), 4.27-3.91 (m, 5H),3.86-3.53 (m, 4H), 3.19 (dd, J=13.7, 10.6 Hz, 1H), 3.13 (s, 3H), 3.01(dd, J=15.2, 10.4 Hz, 1H), 2.89-2.58 (m, 4H), 2.41-2.29 (m, 3H),2.29-2.04 (m, 2H), 2.02-1.59 (m, 7H), 1.36 (d, J=9.7 Hz, 1H), 1.24 (s,1H), 1.01 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H] Calculated forC₃₈H₄₇ClN₄O₆S: 723.21; found 722.71.

Example 231

Example 231 was prepared in a similar manner to Example 75 using5-oxa-2-azaspiro[3.4]octane, triethylamine and Example 109. ¹H NMR (400MHz, DMSO-d₆) δ 7.65 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5, 2.4 Hz, 1H),7.18 (d, J=2.4 Hz, 1H), 7.06 (dd, J=8.2, 1.8 Hz, 1H), 6.92 (d, J=8.1 Hz,1H), 6.86 (d, J=1.9 Hz, 1H), 5.89 (dt, J=14.3, 6.8 Hz, 1H), 5.49 (dd,J=15.2, 8.8 Hz, 1H), 4.14-3.84 (m, 5H), 3.75 (t, J=6.7 Hz, 3H),3.66-3.54 (m, 2H), 3.20 (d, J=14.2 Hz, 1H), 3.13 (s, 3H), 3.01 (dd,J=15.3, 10.4 Hz, 1H), 2.86-2.60 (m, 3H), 2.43-2.28 (m, 2H), 2.29-2.08(m, 2H), 2.07-1.91 (m, 4H), 1.84 (dq, J=11.3, 5.4, 4.1 Hz, 4H), 1.70(ddt, J=23.7, 15.0, 7.1 Hz, 3H), 1.48-1.17 (m, 2H), 1.02 (d, J=6.8 Hz,3H). LCMS-ESI+ (m/z): [M+H] Calculated for C₃₉H₄₉ClN₄O₆S: 737.31; found736.84.

Example 232

Example 232 was synthesized in the same manner as Example 75 withExample 109 and (2S)-2-(methoxymethyl)morpholine; hydrochloride andDIEA. 1H NMR (400 MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd,J=8.5, 2.4 Hz, 1H), 7.15-7.05 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.87 (d,J=2.0 Hz, 1H), 6.00-5.90 (m, 1H), 5.58 (dd, J=15.2, 9.3 Hz, 1H), 4.39(dd, J=14.9, 6.4 Hz, 1H), 4.27-4.02 (m, 4H), 3.89 (dd, J=28.9, 13.1 Hz,2H), 3.76 (dd, J=9.3, 3.7 Hz, 1H), 3.67 (d, J=14.6 Hz, 1H), 3.63-3.41(m, 4H), 3.39 (s, 3H), 3.28-3.23 (m, 4H), 3.12-3.02 (m, 1H), 2.88-2.70(m, 3H), 2.55-2.41 (m, 2H), 2.38-2.26 (m, 1H), 2.23-2.07 (m, 3H),2.00-1.69 (m, 7H), 1.50-1.36 (m, 2H), 1.14 (d, J=6.4 Hz, 3H). LCMS-ESI+(m/z): calcd H+ for C₃₉H₅₁ClN₄O₇S: 755.32; found: 754.99.

Example 233

Example 233 was synthesized in the same manner as Example 75 usingExample 109 and 3-cyanoazetidine hydrogen chloride and triethylamine. ¹HNMR (400 MHz, Acetonitrile-d₃) δ 7.71 (d, J=8.5 Hz, 1H), 7.20 (dd,J=8.5, 2.4 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.00 (dd, J=8.2, 1.9 Hz,1H), 6.91 (d, J=8.1 Hz, 1H), 6.88 (d, J=1.9 Hz, 1H), 5.84 (dt, J=14.1,6.7 Hz, 1H), 5.53 (dd, J=15.2, 9.2 Hz, 1H), 4.32 (dd, J=15.1, 6.4 Hz,1H), 4.24 (s, 2H), 4.14 (s, 2H), 4.05 (d, J=1.9 Hz, 2H), 3.79 (d, J=15.5Hz, 1H), 3.70 (d, J=14.1 Hz, 1H), 3.67-3.61 (m, 1H), 3.55 (tt, J=9.1,6.0 Hz, 1H), 3.39 (dd, J=15.0, 4.9 Hz, 1H), 3.22 (d, J=14.2 Hz, 1H),3.16 (s, 3H), 3.03 (dd, J=15.4, 10.3 Hz, 1H), 2.85-2.66 (m, 2H), 2.42(dd, J=9.4, 5.6 Hz, 1H), 2.33 (dd, J=14.3, 5.9 Hz, 1H), 2.22 (p, J=9.4Hz, 1H), 2.14-1.97 (m, 3H), 1.90-1.61 (m, 6H), 1.45-1.33 (m, 1H), 1.05(d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₃₇H₄₄ClN₅O₅S:706.28; found: 705.8.

Example 234

Example 234 was synthesized in the same manner as Example 75 withExample 109 and 4-(2-methoxyethoxy)piperidine. 1H NMR (400 MHz,Methanol-d4) δ 7.75 (d, J=8.6 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H),7.14-7.06 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H),6.02-5.89 (m, 1H), 5.63-5.52 (m, 1H), 4.37 (dd, J=14.9, 6.3 Hz, 1H),4.13-4.04 (m, 2H), 4.04-3.80 (m, 3H), 3.76 (dd, J=9.3, 3.7 Hz, 1H),3.71-3.51 (m, 7H), 3.39 (s, 3H), 3.30 (s, 1H), 3.28-3.23 (m, 4H), 3.08(dd, J=15.3, 10.3 Hz, 1H), 2.89-2.69 (m, 2H), 2.55-2.40 (m, 2H),2.38-2.26 (m, 1H), 2.23-2.03 (m, 3H), 2.01-1.68 (m, 8H), 1.61-1.29 (m,4H), 1.14 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ forC₄₁H₅₅ClN₄O₇S: 783.35; found: 783.61.

Example 235

Example 235 was synthesized in the same manner as Example 182, using3-ethoxyazetidine instead ofrac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropan-1-amine. 1H NMR (400MHz, Methanol-d4) δ 7.76 (d, J=8.6 Hz, 1H), 7.28-7.04 (m, 3H), 7.01-6.77(m, 2H), 6.03 (s, 1H), 5.54 (dd, J=15.1, 9.4 Hz, 1H), 4.46-4.10 (m, 4H),4.06 (d, J=2.2 Hz, 2H), 3.86 (d, J=14.6 Hz, 2H), 3.78 (dd, J=9.1, 3.5Hz, 1H), 3.66 (d, J=13.9 Hz, 2H), 3.57-3.41 (m, 2H), 3.26 (s, 3H), 3.05(dd, J=15.1, 10.3 Hz, 2H), 2.79 (d, J=18.0 Hz, 2H), 2.48 (s, 2H), 2.36(d, J=9.8 Hz, 2H), 2.12 (d, J=13.4 Hz, 2H), 1.94 (d, J=12.1 Hz, 2H),1.77 (tt, J=17.9, 9.5 Hz, 2H), 1.43 (t, J=13.0 Hz, 1H), 1.31 (s, 3H),1.22 (t, J=7.0 Hz, 2H), 1.12 (d, J=6.2 Hz, 2H), 0.95-0.88 (m, 1H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₄ClN₅O₆S: 725.31; found: 724.71.

Example 236

Example 236 was synthesized in the same manner as Example 75 usingExample 109 and 3-oxa-6-azabicyclo[3.1.1]heptane tosylate. ¹H NMR (400MHz, Methanol-d4) δ 7.75 (d, J=8.6 Hz, 1H), 7.21-7.17 (m, 1H), 7.12 (d,J=2.3 Hz, 2H), 6.93 (d, J=8.2 Hz, 2H), 5.98 (dd, J=14.8, 7.4 Hz, 1H),5.59 (dd, J=15.2, 8.9 Hz, 1H), 4.33 (m, 2H), 4.27 (m, 3H), 4.13-4.01 (m,2H), 3.89-3.80 (m, 3H), 3.77 (dd, J=9.2, 3.7 Hz, 1H), 3.67 (d, J=14.1Hz, 2H), 3.27 (d, J=5.6 Hz, 4H), 3.08 (dd, J=15.4, 10.3 Hz, 1H),2.88-2.74 (m, 2H), 2.66 (q, J=6.9 Hz, 1H), 2.56-2.43 (m, 3H), 2.35 (t,J=9.1 Hz, 1H), 2.25-2.07 (m, 4H), 2.04-1.87 (m, 2H), 1.87-1.70 (m, 3H),1.45 (t, J=12.6 Hz, 1H), 1.14 (d, J=6.5 Hz, 3H). LCMS-ESI+: calc'd forC₃₈H₄₈ClN₄O₆S: 723.29 (M+H); found: 722.97 (M+H).

Example 237

To the mixture of Example 109 (10 mg, 0.017 mmol) in dichloromethane (2mL) was added 4-nitrophenyl chloroformate (6.7 mg, 0.033 mmol), DMAP (8mg, 0.067 mmol), and triethylamine. The reaction mixture was stirred atroom temperature. After 4 hours, 2-(azetidin-3-yl)propan-2-ol (6.7 mg,0.059 mmol) was added and the mixture was continuously stirred for 30minutes. The reaction was concentrated, dissolved in MeOH (2 mL),filtered, and purified by reverse phase preparative HPLC, eluted with60-100% ACN/H2O with 0.1% TFA to afford Example 237. ¹H NMR (400 MHz,Methanol-d₄) δ 7.72 (d, J=8.5 Hz, 1H), 7.25-7.02 (m, 3H), 6.90 (d, J=8.3Hz, 2H), 5.95 (dd, J=14.9, 7.6 Hz, 1H), 5.56 (dd, J=15.2, 9.0 Hz, 1H),4.27 (dd, J=14.9, 6.3 Hz, 1H), 4.11-3.87 (m, 7H), 3.85-3.69 (m, 2H),3.63 (t, J=15.5 Hz, 2H), 3.24 (s, 3H), 3.14-2.98 (m, 1H), 2.88-2.54 (m,3H), 2.54-2.23 (m, 3H), 2.23-2.00 (m, 3H), 2.00-1.62 (m, 7H), 1.42 (t,J=12.8 Hz, 1H), 1.20-1.06 (m, 9H). LCMS-ESI+ (m/z): [M+H] Calculated forC₃₉H₅₁ClN₄O₆S: 739.33; found 738.98.

Example 238

Example 238 was synthesized in the same sequence as Example 284 exceptin Step 1 (9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine;dihydrochloride was used and triethyl amine (2 eq) was also added to thereaction mixture prior to the addition of STAB. ¹H NMR (400 MHz,Methanol-d4) δ 7.71 (d, J=1.9 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.35 (dd,J=8.3, 1.8 Hz, 1H), 7.03 (dd, J=10.5, 2.2 Hz, 2H), 6.86-6.75 (m, 3H),6.22-6.11 (m, 1H), 5.69 (dd, J=15.4, 8.2 Hz, 1H), 4.17-4.08 (m, 1H),4.05-3.90 (m, 7H), 3.84-3.73 (m, 7H), 3.63 (d, J=14.7 Hz, 1H), 3.46 (d,J=14.0 Hz, 1H), 3.24-3.07 (m, 5H), 3.05-2.68 (m, 8H), 2.59-2.38 (m, 4H),2.34-2.21 (m, 3H), 2.07 (d, J=13.7 Hz, 1H), 2.01-1.92 (m, 3H), 1.90-1.81(m, 3H), 1.40-1.30 (m, 1H), 1.16 (d, J=6.2 Hz, 3H). LCMS-ESI+ (m/z):calcd H+ for C₄₆H₅₉ClN₆O₆S: 859.39; found: 859.15.

Example 239

Step 1

Di-tert-butyl-diazene-1,2-dicarboxylate (4.51 g, 19.6 mmol) was added inthree equal portions over 5 min to a stirred mixture of methyl5-formyl-1H-pyrrole-3-carboxylate (2.00 g, 13.1 mmol),2-methylenepropane-1,3-diol (5.32 mL, 65.3 mmol), and triphenylphosphine(6.17 g, 23.5 mmol) in tetrahydrofuran (120 mL) at 0° C., and thereaction mixture was allowed to slowly warm to room temperature. After42 h, the resulting mixture was concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel (0 to43% ethyl acetate in hexanes) to give 239-1.

Step 2

AD-mix-β (14.9 g) was added to a vigorously stirred solution of 239-1(2.06 g, 9.24 mmol) in tert-butyl alcohol (55 mL) and water (55 mL) atroom temperature. After 21 h, saturated aqueous sodium bisulfitesolution (34 mL) was added. After 30 min, brine (50 mL) and water (20mL) were added sequentially. The aqueous layer was extractedsequentially with ethyl acetate (2×200 mL) and dichloromethane (200 mL).The combined organic layers were dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. Methanol (300 mL) wasadded to the aqueous layer, and the resulting inhomogeneous mixture wasfiltered and concentrated under reduced pressure. The filtrate wascombined with the residue from concentration of the combined organiclayers, and the resulting mixture was concentrated under reducedpressure. Methanol (300 mL) and tetrahydrofuran (200 mL) were addedsequentially, and the resulting inhomogeneous layer was trituratedvigorously and then stirred vigorously. After 15 min, the resultingmixture was filtered and was concentrated under reduced pressure.Methanol (100 mL) and tetrahydrofuran (200 mL) were added sequentially.Silica gel (24 g) was added, and the resulting slurry was concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 20% methanol in dichloromethane) togive 239-2.

Step 3

Trifluoracetic acid (3.65 mL, 47.7 mmol) was added via syringe to astirred solution of 239-2 (1.23 g, 4.77 mmol) in dichloromethane (300mL) and methanol (3.87 mL) at room temperature. After 1 min,triethylsilane (8.00 mL, 50.1 mmol) was added via syringe. After 7 min,trifluoroacetic acid (9.13 mL, 119 mmol) and triethylsilane (19.0 mL,119 mmol) were added sequentially via syringe. After 7 h, basic alumina(35 g) was added, and the resulting slurry was concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 9% methanol in dichloromethane) togive 239-3.

Step 4

Di-iso-propy 1-diazene-1,2-dicarboxylate (147 μL, 746 μmol) was addedvia syringe to a stirred mixture of 239-3 (60.0 mg, 249 μmol) andtriphenylphosphine (209 mg, 796 μmol) in toluene (3.0 mL) at roomtemperature, and the resulting mixture was heated to 140° C. in amicrowave reactor. After 30 min, the resulting mixture was cooled toroom temperature and purified by flash column chromatography on silicagel (0 to 48% ethyl acetate in hexanes) to give 239-4.

Step 5

Aqueous sodium hydroxide solution (2.0 M, 400 μL, 800 μmol) was addedvia syringe to a stirred solution of 239-4 (16 mg, 69 μmol) intetrahydrofuran (0.6 mL) and methanol (0.4 mL) at room temperature, andthe resulting mixture was heated to 75° C. After 110 min, the resultingmixture was cooled to room temperature, and aqueous hydrogen chloridesolution (2.0 M, 0.7 mL) and brine (5 mL) were added sequentially. Theaqueous layer was extracted sequentially with dichloromethane (2×15 mL)and ethyl acetate (15 mL). The combined organic layers were dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to give 239-5.

Step 6

Example 239 was synthesized in a manner similar to Example 106 usingIntermediate 359-4 instead of Example 109 and using 239-5 instead of2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid. 1H NMR (400 MHz,Acetone-d6) δ 7.78 (d, J=8.5 Hz, 1H), 7.48 (s, 1H), 7.29-7.13 (m, 4H),7.00 (d, J=8.0 Hz, 1H), 6.31 (s, 1H), 5.93-5.80 (m, 1H), 5.74 (dd,J=15.3, 7.4 Hz, 1H), 4.90 (s, 2H), 4.71 (d, J=7.0 Hz, 2H), 4.51 (dd,J=7.1, 2.8 Hz, 2H), 4.47-4.04 (m, 5H), 3.88 (d, J=15.2 Hz, 1H), 3.74 (d,J=14.3 Hz, 1H), 3.40 (d, J=14.3 Hz, 1H), 3.19 (dd, J=15.3, 8.9 Hz, 1H),2.97-1.63 (m, 15H), 1.56 (d, J=7.1 Hz, 3H), 1.54-1.45 (m, 1H), 1.12-0.99(m, 3H). LCMS: 789.0.

Example 240

Step 1

A vigorously stirred mixture of 106-4 (30.0 mg, 50.2 μmol) and platinum(IV) oxide (5.7 mg, 25.1 μmol) in ethanol (1.5 mL) was placed under anatmosphere of hydrogen gas (1 atm) at room temperature. After 220 min,the resulting mixture was filtered through celite and was concentratedunder reduced pressure to give 240-1.

Step 2

Example 240 was synthesized in a manner similar to Example 106 using240-1 instead of 106-4. 1H NMR (400 MHz, Acetone-d6) δ 8.13 (s, 1H),7.80 (d, J=8.5 Hz, 1H), 7.46 (dd, J=8.2, 1.9 Hz, 1H), 7.41 (d, J=1.9 Hz,1H), 7.26 (dd, J=8.5, 2.4 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 6.94 (d,J=8.2 Hz, 1H), 4.13 (d, J=12.1 Hz, 1H), 4.08 (s, 3H), 4.05 (d, J=12.1Hz, 1H), 3.91 (d, J=14.6 Hz, 1H), 3.86 (s, 3H), 3.74 (t, J=16.3 Hz, 2H),3.46 (d, J=14.4 Hz, 1H), 3.40-3.30 (m, 1H), 3.32 (s, 3H), 3.19 (dd,J=15.1, 9.7 Hz, 1H), 3.07-1.33 (m, 20H), 1.07 (d, J=6.6 Hz, 3H). LCMS:738.1.

Example 241

Step 1

A mixture of 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid (150 mg,0.98 mmol), N-methyltetrahydro-2H-pyran-4-amine (118 mg, 1.03 mmol) andacetic acid (0.11 mL, 1.96 mmol) in DCE (10 mL) was stirred at roomtemperature over two days. Sodium borohydride (74 mg, 1.96 mmol) wasadded and the reaction mixture was stirred at room temperature foranother 16 h. 5 mL of water was added to quench the reaction. It wasthen concentrated to dryness. The crude residue was loaded onto silicagel and purified by column chromatography using 10-50% MeOH in DCM toafford intermediate 241-1. LCMS-ESI+: [M+H]⁺ calc'd for C₁₃H₂₀N₂O₃:253.16; found: 252.82.

Step 2

Example 241 was synthesized in the same manner as Example 18 usingintermediate 241-1 and Example 109. ¹H NMR (400 MHz, Methanol-d4) δ 8.12(d, J=7.6 Hz, 1H), 7.66 (s, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.09 (s, 1H),7.01 (d, J=8.3 Hz, 2H), 6.86 (d, J=8.2 Hz, 1H), 6.14 (d, J=14.7 Hz, 1H),5.65 (t, J=12.0 Hz, 1H), 4.63 (s, 2H), 4.27 (s, 2H), 4.14 (d, J=11.5 Hz,2H), 4.03 (s, 1H), 3.97-3.90 (m, 1H), 3.79 (s, 3H), 3.66 (d, J=14.2 Hz,2H), 3.53 (d, J=12.7 Hz, 2H), 3.31 (s, 3H), 3.27 (s, 2H), 3.19 (s, 2H),2.83 (s, 4H), 2.66 (s, 1H), 2.47 (s, 2H), 2.23 (d, J=7.8 Hz, 2H), 2.11(d, J=11.6 Hz, 2H), 2.00-1.89 (m, 3H), 1.82 (s, 2H), 1.41 (s, 2H), 1.31(s, 3H), 1.15 (d, J=6.3 Hz, 2H), 0.98-0.85 (m, 2H). LCMS-ESI+[M+H]⁺calc'd for C₄₅H₅₈ClN₅O₆S: 832.39; found: 832.40.

Example 242

Example 242 was synthesized in the same manner as Example 75 usingExample 109 and 3-ethylazetidine. 1H NMR (400 MHz, Chloroform-d) δ 7.70(d, J=8.5 Hz, 1H), 7.18 (dd, J=8.5, 2.4 Hz, 1H), 7.12-7.06 (m, 2H),6.94-6.89 (m, 2H), 5.92 (dt, J=13.6, 6.4 Hz, 1H), 5.53 (dd, J=15.2, 8.9Hz, 1H), 4.40 (d, J=14.8 Hz, 1H), 4.18-4.01 (m, 4H), 3.82 (d, J=15.3 Hz,1H), 3.77-3.61 (m, 4H), 3.25 (s, 4H), 2.96 (dd, J=15.2, 10.3 Hz, 1H),2.76 (dd, J=11.6, 4.4 Hz, 2H), 2.63-2.21 (m, 2H), 2.18-1.89 (m, 5H),1.78 (dq, J=17.1, 9.6 Hz, 2H), 1.69-1.57 (m, 3H), 1.38 (q, J=12.9, 11.5Hz, 1H), 1.25 (s, 1H), 1.09 (d, J=6.4 Hz, 3H), 0.89 (t, J=7.3 Hz, 3H).LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₃₈H₄₉ClN₄O₅S: 709.31; found:708.95.

Example 243

Example 243 was synthesized in the same manner as Example 75 usingExample 109 and (1S,2S)-2-(trifluoromethyl)cyclopropan-1-aminehydrochloride. ¹H NMR (400 MHz, Methanol-d4) δ 7.77-7.67 (m, 1H), 7.17(d, J=8.0 Hz, 1H), 7.10 (s, 2H), 6.96-6.87 (m, 2H), 6.02 (t, J=7.9 Hz,1H), 5.61 (dd, J=15.1, 8.9 Hz, 1H), 4.26 (d, J=13.3 Hz, 1H), 4.05 (s,2H), 3.87-3.68 (m, 2H), 3.66 (d, J=14.2 Hz, 1H), 3.28 (m, 4H), 3.12-3.06(m, 1H), 3.03 (dd, J=7.9, 4.6 Hz, 1H), 2.84 (d, J=16.2 Hz, 1H),2.79-2.69 (m, 1H), 2.48 (d, J=15.1 Hz, 2H), 2.38 (s, 1H), 2.32-2.15 (m,1H), 2.10 (d, J=13.6 Hz, 1H), 2.06-1.92 (m, 2H), 1.87 (d, J=10.6 Hz,1H), 1.80 (q, J=6.8, 5.7 Hz, 1H), 1.62 (m, 1H), 1.40 (dd, J=25.6, 13.0Hz, 2H), 1.31 (d, J=3.7 Hz, 2H), 1.20 (dt, J=7.6, 6.1 Hz, 1H), 1.15 (m,4H). LCMS-ESI+: calc'd for C₃₇H₄₅ClF₃N₄O₅S: 749.27 (M+H); found: 749.40(M+H).

Example 244

Diphenyl carbonate (29.4 mg, 137 μmol) was added to a stirred mixture of240-1 (9.5 mg, 16 μmol) and 4-(dimethylamino)pyridine (9.7 mg, 79 μmol)in acetonitrile (0.6 mL) at room temperature. After 21 h,4-methoxyazetidine hydrochloride (48.9 mg, 396 μmol) andN,N-diisopropylethylamine (152 μL, 871 μmol) were added sequentially,and the resulting mixture was heated to 55° C. After 150 min, theresulting mixture was cooled to room temperature and was purified byreverse phase preparative HPLC (0.1% trifluoroacetic acid inacetonitrile/water) to give Example 244. 1H NMR (400 MHz, Acetone-d6) δ7.79 (d, J=8.6 Hz, 1H), 7.31-7.21 (m, 2H), 7.17-7.11 (m, 2H), 6.98 (d,J=8.1 Hz, 1H), 4.35-3.78 (m, 7H), 3.73 (d, J=14.3 Hz, 1H), 3.49-3.22 (m,4H), 3.30 (s, 3H), 3.24 (s, 3H), 3.16 (dd, J=15.4, 8.6 Hz, 1H),2.92-1.25 (m, 16H), 1.12 (d, J=6.7 Hz, 3H). LCMS: 713.1.

Example 245

Example 245 was synthesized in the same manner as Example 75 usingExample 109 and methyl piperazine-1-carboxylate. 1H NMR (400 MHz,Methanol-d4) δ 7.74 (d, J=8.6 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H),7.14-7.06 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H),6.00-5.89 (m, 1H), 5.58 (dd, J=15.2, 9.3 Hz, 1H), 4.39 (dd, J=14.9, 6.4Hz, 1H), 4.12-4.02 (m, 2H), 3.85 (d, J=15.1 Hz, 1H), 3.79-3.71 (m, 4H),3.70-3.56 (m, 5H), 3.53-3.43 (m, 4H), 3.27-3.24 (m, 4H), 3.08 (dd,J=15.3, 10.3 Hz, 1H), 2.87-2.71 (m, 2H), 2.54-2.41 (m, 2H), 2.37-2.26(m, 1H), 2.23-2.07 (m, 3H), 2.00-1.86 (m, 3H), 1.86-1.68 (m, 4H),1.50-1.37 (m, 1H), 1.14 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ forC₃₉H₅₀ClN₅O₇S:768.31; found: 767.73.

Example 246

Example 246 was synthesized in the same manner as Example 237 usingExample 109 and 3-methoxy-3-(trifluoromethyl)azetidine hydrochloride. ¹HNMR (400 MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.4,2.4 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.09 (dd, J=8.1, 1.9 Hz, 1H), 6.94(d, J=8.1 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 5.96 (dt, J=14.3, 6.8 Hz,1H), 5.59 (dd, J=15.2, 9.2 Hz, 1H), 4.35 (dd, J=14.9, 6.4 Hz, 1H), 4.15(d, J=24.8 Hz, 5H), 4.09 (d, J=1.2 Hz, 2H), 3.85 (d, J=15.1 Hz, 1H),3.76 (dd, J=9.2, 3.7 Hz, 1H), 3.64 (dd, J=23.7, 14.6 Hz, 2H), 3.53 (d,J=1.1 Hz, 3H), 3.26 (m, 4H), 3.08 (dd, J=15.3, 10.3 Hz, 1H), 2.90-2.65(m, 2H), 2.46 (dd, J=14.8, 5.5 Hz, 2H), 2.33 (p, J=9.1 Hz, 1H), 2.19(dt, J=14.6, 7.2 Hz, 1H), 2.12 (d, J=12.9 Hz, 2H), 2.03-1.86 (m, 1H),1.79 (tt, J=17.7, 9.6 Hz, 3H), 1.45 (t, J=12.5 Hz, 1H), 1.33 (d, J=16.3Hz, 1H), 1.15 (d, J=6.7 Hz, 3H). LCMS-ESI+: calc'd for C₃₈H₄₇ClF₃N₄O₆S:779.28 (M+H); found: 779.62 (M+H).

Example 247

Example 247 was prepared in a similar manner to Example 237 using1-(piperazin-1-yl)ethan-1-one, triethylamine and Example 109. LCMS-ESI+(m/z): [M+H] Calculated for C₃₉H₅₀ClN₅O₆S: 752.32; found 751.80.

Example 248

Example 248 was prepared in a similar manner to Example 237 using5,8-dioxa-2-azaspiro[3.5]nonane, triethylamine and Example 109.LCMS-ESI+ (m/z): [M+H] Calculated for C₃₉H₄₉ClN₄O₇S: 753.30; found752.88.

Example 249

To a stirred solution of Example 359 (60 mg, 0.081 mmol) in aceticanhydride (10 mL) was heated at 60° C. for 4 hours. Water was added andthe mixture was extracted with dichloromethane. The organic phase wasdried over anhydrous magnesium sulfate and the solvent was removed underreduced pressure, and purified on reversed phase chromatography 0.1% TFA70-95% acetonitrile to yield Example 249. 1H NMR (400 MHz, Chloroform-d)δ 7.86-7.61 (m, 3H), 7.35-7.15 (m, 3H), 7.10 (d, J=2.3 Hz, 1H), 6.93 (d,J=8.3 Hz, 1H), 5.83 (s, 1H), 5.60 (dd, J=15.4, 6.7 Hz, 1H), 5.37-5.17(m, 1H), 4.21-3.96 (m, 5H), 3.92 (d, J=15.2 Hz, 1H), 3.82 (d, J=12.5 Hz,3H), 3.75-3.63 (m, 2H), 3.26 (d, J=14.7 Hz, 1H), 3.01 (dd, J=15.6, 7.5Hz, 1H), 2.78 (dd, J=10.7, 5.1 Hz, 2H), 2.63-2.46 (m, 2H), 2.16 (d,J=16.3 Hz, 3H), 2.01-1.82 (m, 4H), 1.82-1.63 (m, 3H), 1.57 (d, J=7.2 Hz,3H), 1.42 (d, J=9.3 Hz, 2H), 1.26 (d, J=13.1 Hz, 4H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₄₀H₄₈ClN₅O₇S: 778.30; found: 778.35.

Example 250 Step 1

To a solution of tert-butyl(2R,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (50 mg, 0.267 mmol) indry THF (1.3 mL), was added 60% sodium hydride (oil dispersion) (15 mg,0.401 mmol). The temperature of the mixture was maintained at 0° C.After addition was completed, stirring was continued at the sametemperature for 10 min. Then iodomethane (0.02 mL, 0.321 mmol) was addeddropwise and the temperature was allowed to rise to rt. The reactionmixture was stirred at this temperature for 1 h. Solvent was removedunder reduced pressure to give tert-butyl(2R,3S)-3-methoxy-2-methylazetidine-1-carboxylate.

Step 2

To a solution of tert-butyl (2R,3 S)-3-methoxy-2-methylazetidine-1-carboxylate (53.7 mg, 0.267 mmol) inisopropyl alcohol (1.65 mL), was added a solution of hydrogen chloridein dioxane (4 M, 0.2 mL, 0.8 mmol). The reaction mixture was stirred at50° C. for 25 h. Solvent was removed under reduced pressure to give(2R,3S)-3-methoxy-2-methylazetidine hydrochloride.

Step 3

To a solution of Example 109 (10 mg, 0.0167 mmol), nitrophenylchloroformate (4.04 mg, 0.0201 mmol), and DMAP (4.08 mg, 0.0334 mmol) inDCM (0.4 mL), was added triethylamine (0.04 mL, 0.29 mmol) and stirredat rt for 4 h. A solution of (2R,3S)-3-methoxy-2-methylazetidinehydrochloride (11.5 mg, 0.0836 mmol) and triethylamine (0.05 mL, 0.359mmol) in DCM (0.4 mL) was added, and stirred for 1 h. Solvent wasremoved under reduced pressure, residue was redissolved in DMSO (2 mL)and purified by Gilson reverse phase prep HPLC, and eluted with 50-100%ACN/H₂O with 0.1% TFA to afford Example 250. 1H NMR (400 MHz,Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5, 2.4 Hz, 1H),7.12-7.07 (m, 2H), 6.91 (d, J=8.1 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 5.95(dt, J=14.4, 6.6 Hz, 1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 4.31 (dd,J=14.8, 6.2 Hz, 1H), 4.23-4.11 (m, 2H), 4.06 (d, J=1.8 Hz, 2H), 3.83 (d,J=15.1 Hz, 1H), 3.77-3.71 (m, 3H), 3.65 (d, J=14.2 Hz, 1H), 3.61-3.52(m, 1H), 3.24 (s, 3H), 3.06 (dd, J=15.3, 10.3 Hz, 1H), 2.90-2.62 (m,2H), 2.54-2.39 (m, 2H), 2.39-2.22 (m, 1H), 2.22-2.02 (m, 3H), 1.97-1.63(m, 6H), 1.50-1.38 (m, 4H), 1.13 (d, J=6.4 Hz, 3H). LCMS-ESI+ (m/z):[M+H]⁺ calculated for C₃₈H₄₉ClN₄O₆S: 725.31; found: 724.92.

Example 251

Example 251 was prepared in the same manner as Example 362 with Example109 and 3-(2-methoxyethoxy)azetidine hydrochloride. LCMS-ESI+ (m/z):[M+H]⁺ calc'd for C₃₉H₅₁ClN₄O₇S: 755.3240; found: 754.79. ¹H NMR (400MHz, Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.6, 2.4 Hz,1H), 7.13-7.06 (m, 2H), 6.95-6.85 (m, 2H), 5.96 (dt, J=14.1, 6.7 Hz,1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 4.40-4.13 (m, 4H), 4.12-4.00 (m,2H), 3.98-3.80 (m, 3H), 3.74 (dd, J=9.2, 3.7 Hz, 1H), 3.65 (d, J=14.2Hz, 1H), 3.62-3.52 (m, 5H), 3.37 (s, 3H), 3.29-3.25 (m, 1H), 3.24 (s,3H), 3.06 (dd, J=15.3, 10.3 Hz, 1H), 2.87-2.69 (m, 2H), 2.52-2.41 (m,2H), 2.32 (p, J=8.6, 7.9 Hz, 1H), 2.24-2.04 (m, 3H), 2.00-1.66 (m, 6H),1.42 (t, J=12.7 Hz, 1H), 1.13 (d, J=6.6 Hz, 3H).

Example 252

Step 1

To a suspension of ethyl 3-methoxy-1H-pyrazole-4-carboxylate (350 mg,2.05 mmol) in dioxane (1 mL) and water (0.7 mL), was added KOH (346 mg,6.17 mmol). To stirred mixture was bubbled CHIF₂ gas over 30 min. TwoRegioisomer products were formed with same Mass at 221 (RT=0.39 and0.49). The reaction mixture was diluted with ether (50 mL), washed withwater followed by brine solution. The organic extract was dried oversodium sulfate to give crude product which was carried onto the nextstep without purification. LCMS-ESI+ (m/z): [M+H] Calculated forC₈H₁₁F₂N₃O₂: 220.08; found 220.90.

Step 2

To a suspension of ethyl1-(difluoromethyl)-3-methoxy-1H-pyrazole-4-carboxylate (300 mg, 1.36mmol) in MeOH (3 mL), THF (10 mL) was added 2 N NaOH solution (3 mL).The reaction mixture was stirred at 50° C. for 90 min. Solvent wasconcentrated, and the crude residue was dissolved in water (30 mL). Thissolution was acidified with 1.5 N HCl by drop wise addition to maintainpH 2-3 and stirred for 5 min. The product was filtered, washed withwater, and dried. The crude product1-(difluoromethyl)-3-methoxy-1H-pyrazole-4-carboxylic acid was used fornext step. LCMS-ESI+ (m/z): [M+H] Calculated for C₆H₆F₂N₂O₃: 193.03;found 193.02.

Step-3

Example 252 synthesized in the same manner as Example 18 using1-(difluoromethyl)-3-methoxy-1H-pyrazole-4-carboxylic acid and Example109. ¹H NMR (400 MHz, Methanol-d₄) δ 8.50 (s, 1H), 7.75 (d, J=8.5 Hz,1H), 7.57-7.23 (m, 1H), 7.23-7.20 (m, 1H), 7.17 (dd, J=8.5, 2.4 Hz, 1H),7.11 (d, J=2.3 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H),6.05 (dt, J=14.2, 6.5 Hz, 1H), 5.61 (dd, J=15.3, 8.6 Hz, 1H), 4.29 (dd,J=14.9, 6.0 Hz, 1H), 4.07 (d, J=2.4 Hz, 5H), 3.99-3.62 (m, 5H), 3.36 (s,1H), 3.28 (s, 3H), 3.16-3.00 (m, 1H), 2.79 (dddd, J=22.7, 16.7, 11.7,5.2 Hz, 2H), 2.60-2.33 (m, 2H), 2.32-2.04 (m, 3H), 2.03-1.86 (m, 3H),1.78 (qd, J=9.4, 8.5, 5.3 Hz, 3H), 1.44 (ddd, J=14.2, 11.7, 3.1 Hz, 1H),1.15 (d, J=6.2 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₈H₄₄ClF₂N₅O₆S: 772.27; found: 772.04.

Example 253

Example 253 was synthesized in the same manner as Example 250 usingtert-butyl (2S,3R)-3-hydroxy-2-methylazetidine-1-carboxylate and Example109. 1H NMR (400 MHz, Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.17 (dd,J=8.5, 2.3 Hz, 1H), 7.09 (dd, J=7.8, 2.0 Hz, 2H), 6.92 (d, J=8.1 Hz,1H), 6.88 (s, 1H), 5.94 (dt, J=14.2, 6.7 Hz, 1H), 5.56 (dd, J=15.2, 9.2Hz, 1H), 4.30 (dd, J=14.9, 6.2 Hz, 1H), 4.19-4.13 (m, 1H), 4.06 (d,J=1.2 Hz, 2H), 3.83 (d, J=15.2 Hz, 1H), 3.77-3.69 (m, 3H), 3.65 (d,J=14.1 Hz, 1H), 3.24 (s, 3H), 3.16-2.99 (m, 1H), 2.88-2.69 (m, 2H), 2.66(s, 0H), 2.52-2.37 (m, 1H), 2.33 (q, J=9.0 Hz, 1H), 2.23-2.02 (m, 3H),2.00-1.64 (m, 4H), 1.47 (d, J=6.5 Hz, 3H), 1.44-1.24 (m, 2H), 1.14 (d,J=6.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₃₈H₄₉ClN₄O₆S:725.31; found: 724.93.

Example 254

Example 359 (10 mg, 0.14 mmol),(((9H-fluoren-9-yl)methoxy)carbonyl)-L-valine (9.21 mg, 0.02 mmol),EDCI.HCl (6.5 mg, 0.034 mmol), and DMAP (3.3 mg, 0.027 mmol) werecombined in a 8 mL vial, and DCM (3 mL) was added. This mixture wassonicated for 3 min for complete dissolution and stirred at 0° C. for 2h. The solvent was concentrated, and to the crud product was added 20%piperidine in DMF (2 mL). This solution was stirred at RT for 20 min.The reaction mixture was filtered and purified by reverse phasepreparative HPLC, eluted with 60-100% ACN/H₂O with 0.1% TFA to affordExample 254. ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 3H), 7.98 (s, 1H),7.63 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.4, 2.3 Hz, 1H), 7.16 (d, J=2.3 Hz,1H), 7.05 (d, J=8.2 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.89 (s, 1H), 6.51(s, 2H), 5.98 (t, J=12.5 Hz, 1H), 5.79 (dd, J=15.1, 8.7 Hz, 1H), 5.42(dd, J=8.7, 3.3 Hz, 1H), 4.15-3.94 (m, 3H), 3.95-3.85 (m, 2H), 3.81 (s,4H), 3.70 (s, 3H), 3.58 (d, J=14.0 Hz, 1H), 3.25-2.94 (m, 2H), 2.85-2.59(m, 2H), 2.35 (d, J=35.9 Hz, 1H), 2.21-1.60 (m, 10H), 1.42 (d, J=7.0 Hz,4H), 1.03 (d, J=5.9 Hz, 3H), 0.96 (dd, J=12.0, 6.9 Hz, 6H). LCMS-ESI+(m/z): [M+H]+ calcd for C₄₃H₅₅ClN₆O₇S: 835.35; found: 834.95.

Example 255 Step 1

A stirred mixture of 5-formyl-1H-pyrrole-3-carboxylate (500 mg, 3.27mmol), 1-chloro-2-methyl-2-propene (639 μL, 6.53 mmol), and cesiumcarbonate (2.03 g, 6.24 mmol) in acetonitrile (6 mL) was heated to 65°C. After 150 min, the resulting mixture was cooled to room temperature,and water (30 mL), brine (20 mL), and saturated aqueous ammoniumchloride solution (10 mL) were added sequentially. The aqueous layer wasextracted with dichloromethane (2×60 mL). The combined organic layerswere dried over anhydrous magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 25% ethyl acetate in hexanes) to give255-1.

Step 2

Osmium tetroxide solution (2.5% wt. in tert-butyl alcohol, 234 μL, 19μmol) was added over 1 min via syringe to a stirred mixture of 255-1(387 mg, 1.87 mmol), 4-(dimethylamino)pyridine (6.9 mg, 56 μmol), and4-methylmorpholine-A-oxide (328 mg, 2.80 mmol) in tert-butyl alcohol(3.0 mL), water (1.0 mL), and tetrahydrofuran (1.0 mL) at roomtemperature. After 74 min, the resulting mixture was heated to 90° C.After 76 min, the resulting mixture was cooled to room temperature, andsodium sulfite (471 mg) and water (1.0 mL) were added sequentially.After 20 min, the resulting mixture was filtered through celite, and thefilter cake was extracted with ethyl acetate (100 mL). The combinedfiltrates were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 100% ethyl acetate indichloromethane) to give 255-2.

Step 3

Trifluoroacetic acid (1.43 mL, 18.7 mmol) was added via syringe to astirred solution of 255-2 (451 mg, 1.87 mmol) in dichloromethane (117mL) and methanol (1.52 mL) at room temperature. After 1 min,triethylsilane (3.14 mL, 19.6 mmol) was added via syringe. After 19 min,trifluoroacetic acid (3.58 mL, 46.8 mmol) and triethylsilane (7.48 mL,46.7 mmol) were added sequentially via syringe. After 55 min, saturatedaqueous sodium carbonate solution (55 mL) was added, and the resultingbiphasic mixture was stirred vigorously. After 15 min, brine (30 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane (60 mL). The combined organic layers were driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 70% ethyl acetate in hexanes) to give255-3.

Step 4

Potassium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran,466 μL, 466 μmol) was added via syringe to a stirred solution of 255-3(35.0 mg, 155 μmol) in tetrahydrofuran at 0° C. After 6 min, iodomethane(48.5 μL, 777 μmol) was added via syringe, and the resulting mixture waswarmed to room temperature. After 25 min, saturated aqueous ammoniumchloride solution (5 mL) and ethyl acetate (30 mL) were addedsequentially. The organic layer was washed with water (20 mL), was driedover anhydrous magnesium sulfate, was filtered, and was concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 40% ethyl acetate in hexanes) to give255-4.

Step 5

Aqueous sodium hydroxide solution (2.0 M, 900 μL, 1.80 mmol) was addedvia syringe to a stirred solution of 255-4 (37.0 mg, 155 μmol) intetrahydrofuran (0.65 mL) and methanol (1.5 mL) at room temperature, andthe resulting mixture was heated to 70° C. After 16 h, the resultingmixture was cooled to room temperature, and aqueous hydrogen chloridesolution (2.0 M, 1.0 mL) and brine (10 mL) were added sequentially. Theaqueous layer was extracted sequentially with dichloromethane (2×15 mL)and ethyl acetate (15 mL). The combined organic layers were dried overanhydrous magnesium sulfate, were filtered, and were concentrated underreduced pressure to give 255-5.

Step 6: Preparation of Example 255

Example 255 was synthesized in a manner similar to Example 106 usingIntermediate 359-4 instead of 106-4 and using 255-5 instead of2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid. 1H NMR (400 MHz,Acetone-d6) δ 7.78 (d, J=8.6 Hz, 1H), 7.45-7.12 (m, 5H), 6.97 (s, 1H),6.30 (s, 1H), 5.99-5.83 (m, 1H), 5.83-5.69 (m, 1H), 4.80 (s, 2H),4.24-3.38 (m, 11H), 3.36 (s, 3H), 3.19 (dd, J=15.4, 9.0 Hz, 1H),2.98-1.14 (m, 21H), 1.14-1.04 (m, 3H). LCMS: 805.1.

Example 256

Example 256 was synthesized in the same manner as Example 237 usingExample 109 and (R)-3-(methoxymethyl)pyrrolidine. ¹H NMR (400 MHz,Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H),7.12 (td, J=3.8, 1.8 Hz, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.91 (d, J=2.0 Hz,1H), 5.97 (dt, J=14.1, 6.5 Hz, 1H), 5.58 (dd, J=15.2, 9.1 Hz, 1H), 4.33(dd, J=14.8, 5.9 Hz, 1H), 4.08 (d, J=1.8 Hz, 2H), 3.90-3.81 (m, 1H),3.76 (dd, J=9.2, 3.7 Hz, 1H), 3.67 (m, 2H), 3.63-3.52 (m, 2H), 3.42 (d,J=8.1 Hz, 1H), 3.37 (m, 4H), 3.26 (s, 4H), 3.22-3.14 (m, 1H), 3.08 (dd,J=15.2, 10.3 Hz, 1H), 2.90-2.70 (m, 2H), 2.59-2.40 (m, 4H), 2.35 (q,J=9.0 Hz, 1H), 2.17 (m, 3H), 2.07 (m, 1H), 2.01-1.86 (m, 4H), 1.77 (m,4H), 1.44 (t, J=12.5 Hz, 1H), 1.15 (d, J=6.3 Hz, 3H). LCMS-ESI+: calc'dfor C₃₉H₅₂ClN₄O₆S: 739.32 (M+H); found: 739.80 (M+H).

Example 257

Example 257 was synthesized in the same manner as Example 237 usingExample 109 and 6-methoxy-2-azaspiro[3.3]heptane hydrochloride. ¹H NMR(400 MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4Hz, 1H), 7.13 (dd, J=6.4, 2.1 Hz, 2H), 6.96-6.87 (m, 2H), 5.98 (dt,J=14.3, 6.8 Hz, 1H), 5.58 (dd, J=15.2, 9.1 Hz, 1H), 4.29 (dd, J=14.9,6.4 Hz, 1H), 4.15-4.04 (m, 2H), 4.00 (m, 4H), 3.90-3.79 (m, 2H), 3.76(dd, J=9.1, 3.7 Hz, 1H), 3.67 (d, J=14.2 Hz, 1H), 3.65-3.57 (m, 1H),3.26 (m, 4H), 3.24 (s, 3H), 3.08 (dd, J=15.2, 10.3 Hz, 1H), 2.89-2.70(m, 2H), 2.57-2.42 (m, 4H), 2.35 (q, J=9.0 Hz, 1H), 2.24-2.15 (m, 1H),2.15-2.06 (m, 3H), 1.93 (m, 3H), 1.77 (m, 4H), 1.44 (t, J=12.5 Hz, 1H),1.33 (d, J=16.3 Hz, 1H), 1.14 (d, J=6.6 Hz, 3H). LCMS-ESI+: calc'd forC₄₀H₅₂ClN₄O₆S: 752.32 (M+H); found: 751.53 (M+H).

Example 258 was synthesized in the same manner as Example 237 usingExample 109 and 4-(difluoromethyl)piperidine hydrochloride. ¹H NMR (400MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz,1H), 7.12 (d, J=2.3 Hz, 1H), 7.09 (dd, J=8.1, 1.9 Hz, 1H), 6.94 (d,J=8.1 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 5.95 (dt, J=14.2, 6.7 Hz, 1H),5.89-5.61 (m, 1H), 5.61-5.53 (m, 1H), 4.45 (s, 2H), 4.38 (dd, J=14.9,6.3 Hz, 1H), 4.09 (s, 2H), 3.85 (d, J=15.2 Hz, 1H), 3.76 (dd, J=9.3, 3.7Hz, 1H), 3.67 (d, J=14.2 Hz, 1H), 3.60 (dd, J=14.9, 5.8 Hz, 1H), 3.28(m, 6H), 3.08 (dd, J=15.3, 10.3 Hz, 1H), 2.98-2.68 (m, 4H), 2.46 (dd,J=14.4, 5.3 Hz, 1H), 2.32 (p, J=9.2 Hz, 1H), 2.19 (q, J=7.6 Hz, 1H),2.12 (d, J=15.9 Hz, 2H), 2.01-1.86 (m, 1H), 1.86-1.65 (m, 7H), 1.52-1.28(m, 2H), 1.14 (d, J=6.6 Hz, 3H). LCMS-ESI+: calc'd for C₃₉H₅₀ClF₂N₄O₅S:759.31 (M+H); found: 759.33 (M+H).

Example 259

Step 1

Dess-Martin periodinane (85.4 mg, 201 μmol) was added to a stirredsolution of 255-3 (32.4 mg, 144 μmol) in dichloromethane (1.0 mL) atroom temperature. After 45 min, aqueous sodium thiosulfate solution (1.0M, 1.0 mL), saturated sodium bicarbonate solution (5.0 mL), diethylether (60 mL), and ethyl acetate (60 mL) were added sequentially. Theorganic layer was washed sequentially with water (50 mL), a mixture ofwater and saturated aqueous sodium bicarbonate solution (1:1 v:v, 50mL), and water (50 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue wasdissolved in dichloromethane (2.0 mL) and stirred at room temperature.Morpholine (88.1 μL, 1.01 mmol) acetic acid (57.6 μL, 1.01 mmol), andsodium triacetoxyborohydride (213 mg, 1.01 mmol) were addedsequentially, and the resulting mixture was heated to 45° C. After 45min, the resulting mixture was cooled to room temperature, and saturatedaqueous sodium carbonate solution (6.0 mL) and ethyl acetate (75 mL)were added sequentially. The organic layer was washed with a mixture ofwater and brine (3:1 v:v, 50 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (0 to 9%methanol in dichloromethane) to give 259-1.

Step 2: Preparation of Example 259

Example 259 was synthesized in a manner similar to Example 229 using259-1 instead of 229-3. 1H NMR (400 MHz, Acetone-d6) δ 7.79 (d, J=8.5Hz, 1H), 7.44 (s, 1H), 7.28-7.16 (m, 3H), 7.15 (d, J=2.4 Hz, 1H), 7.00(d, J=8.0 Hz, 1H), 6.33 (s, 1H), 5.95-5.82 (m, 1H), 5.74 (dd, J=15.3,7.3 Hz, 1H), 4.90-4.76 (m, 2H), 4.48-3.59 (m, 16H), 3.40 (d, J=14.3 Hz,1H), 3.19 (dd, J=15.2, 8.9 Hz, 1H), 3.10-1.42 (m, 15H), 1.56 (d, J=7.1Hz, 3H), 1.32 (d, J=1.5 Hz, 3H), 1.05 (s, 3H). LCMS: 860.1.

Example 260

Example 260 was synthesized in the same manner as Example 75 usingExample 359 and (1R,2R)-2-(difluoromethyl)cyclopropan-1-aminehydrochloride. ¹H NMR (400 MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H),7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.12 (d, J=2.3 Hz,1H), 6.99-6.92 (m, 2H), 5.99-5.79 (m, 2H), 5.79-5.65 (m, 1H), 4.42-4.26(m, 1H), 4.20 (dd, J=8.5, 3.3 Hz, 1H), 4.10 (s, 2H), 3.84 (d, J=15.1 Hz,1H), 3.66 (d, J=14.3 Hz, 1H), 3.29 (m, 1H), 3.15-3.06 (m, 1H), 2.96-2.68(m, 3H), 2.50-2.35 (m, 1H), 2.31 (t, J=9.0 Hz, 1H), 2.17 (s, 2H), 2.11(m, 2H), 2.03-1.91 (m, 2H), 1.91-1.81 (m, 2H), 1.75 (q, J=9.2 Hz, 1H),1.66-1.42 (m, 5H), 1.23-1.00 (m, 4H), 1.00-0.88 (m, 1H). LCMS-ESI+:calc'd for C₃₇H₄₆ClF₂N₄O₅S: 731.28 (M+H); found: 731.11 (M+H).

Example 261

Example 261 was synthesized in the same manner as Example 182, using3-(oxetan-3-yl)azetidine instead ofrac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropan-1-amine. 1H NMR (400MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.3 Hz,1H), 7.12 (dt, J=4.3, 1.9 Hz, 2H), 7.00-6.86 (m, 2H), 5.98 (dt, J=14.2,6.7 Hz, 1H), 5.58 (dd, J=15.2, 9.1 Hz, 1H), 4.45 (t, J=6.0 Hz, 2H),4.37-4.12 (m, 3H), 4.08 (d, J=2.1 Hz, 2H), 3.92-3.71 (m, 3H), 3.71-3.55(m, 2H), 3.26 (s, 3H), 3.08 (dd, J=15.2, 10.3 Hz, 2H), 3.01 (s, 2H),2.91-2.66 (m, 3H), 2.47 (dd, J=12.2, 7.9 Hz, 2H), 2.38-2.29 (m, 1H),2.26-2.05 (m, 3H), 1.97-1.88 (m, 2H), 1.78 (tt, J=17.1, 9.5 Hz, 3H),1.45 (t, J=11.8 Hz, 2H), 1.31 (s, 2H), 1.15 (d, J=6.6 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₉H₄₉ClN₄O₆S: 737.31; found: 737.06.

Example 262

Step 1: Preparation of Ethyl1-cyclopropyl-3-methoxy-1H-pyrazole-4-carboxylate

The reaction mixture of ethyl 3-methoxy-1H-pyrazole-4-carboxylate (113mg, 0.66 mmol), cyclopropylboronic acid (114 mg, 1.33 mmol), copper(II)acetate (120.61 mg, 0.66 mmol), 2,2′-bipyridyl (103.71 mg, 0.66 mmol)and sodium carbonate (140.76 mg, 1.33 mmol) in toluene (5 mL) was heatedat 60° C. overnight with exposure to air. The reaction mixture wascooled down and filtered. The filtrate was concentrated down andpurified by silica gel chromatograph (eluting with 0-100% EtOAc/hexane)to give the title compound (105 mg).

Step 2: Preparation of 1-cyclopropyl-3-methoxy-1H-pyrazole-4-carboxylicAcid

The reaction mixture of ethyl1-cyclopropyl-3-methoxy-pyrazole-4-carboxylate (12 mg, 0.057 mmol), 2 MNaOH (0.057 mL) in MeOH (1.0 mL) and water (0.5 mL) was stirred at 45°C. overnight. The reaction mixture was concentrated and used in the nextstep without purification.

Step 3

Example 262 was synthesized in the same manner as Example 18, usingExample 109 instead of Example 5, and2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylic acid was used instead of3-methoxypropionic acid. 1H NMR (400 MHz, Methanol-d4) δ 8.14 (s, 1H),7.77 (d, J=8.6 Hz, 1H), 7.37-7.30 (m, 1H), 7.23-7.09 (m, 3H), 6.92 (d,J=8.2 Hz, 1H), 6.11 (dt, J=14.1, 6.4 Hz, 1H), 5.62 (dd, J=15.3, 8.2 Hz,1H), 4.19-3.95 (m, 6H), 3.87 (d, J=15.0 Hz, 1H), 3.79 (dd, J=8.1, 3.3Hz, 1H), 3.71 (d, J=14.3 Hz, 1H), 3.63 (tt, J=7.4, 3.8 Hz, 1H), 3.38 (d,J=14.2 Hz, 1H), 3.29 (s, 3H), 3.08 (dd, J=15.0, 9.9 Hz, 1H), 2.92-2.71(m, 3H), 2.51 (ddd, J=22.6, 9.8, 5.5 Hz, 3H), 2.30-2.19 (m, 2H), 2.12(d, J=13.6 Hz, 1H), 1.94 (d, J=13.6 Hz, 3H), 1.78 (d, J=6.7 Hz, 3H),1.51-1.40 (m, 1H), 1.17-1.07 (m, 5H), 1.07-1.00 (m, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C₄₀H₄₈ClN₅O₆S: 762.30; found: 760.83.

Example 263

Example 263 was synthesized in the same manner as Example 182, using3-(cyclopropoxy)azetidine hydrochloride instead ofrac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropan-1-amine. 1H NMR (400MHz, Methanol-d4) δ 7.75 (d, J=8.6 Hz, 1H), 7.19 (dd, J=8.6, 2.4 Hz,1H), 7.12 (dt, J=4.3, 2.6 Hz, 2H), 6.93 (d, J=8.2 Hz, 2H), 5.97 (dt,J=14.2, 6.8 Hz, 1H), 5.58 (dd, J=15.2, 9.1 Hz, 1H), 4.48-4.39 (m, 1H),4.38-4.15 (m, 3H), 4.08 (d, J=1.9 Hz, 2H), 4.01-3.80 (m, 3H), 3.76 (dd,J=9.1, 3.6 Hz, 1H), 3.67 (d, J=14.3 Hz, 2H), 3.36 (d, J=3.1 Hz, 1H),3.26 (s, 3H), 3.08 (dd, J=15.3, 10.3 Hz, 1H), 2.88-2.70 (m, 2H),2.52-2.42 (m, 2H), 2.35 (q, J=9.2 Hz, 1H), 2.25-2.04 (m, 3H), 2.01-1.69(m, 5H), 1.44 (t, J=12.5 Hz, 1H), 1.31 (s, 3H), 1.15 (d, J=6.6 Hz, 2H),0.96-0.88 (m, 1H), 0.68-0.58 (m, 2H), 0.58-0.46 (m, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₉H₄₉ClN₄O₆S: 737.31; found: 735.76.

Example 264

Step 1

Di(1H-imidazol-1-yl)methanethione (58.6 mg, 329 μmol) was added to astirred mixture of 255-3 (37.0 mg, 164 μmol) and4-(dimethylamino)pyridine (10 mg, 82 μmol) in tetrahydrofuran at roomtemperature. After 5 min, the resulting mixture was heated to 65° C.After 35 min, the resulting mixture was heated to 80° C. After 23 h, theresulting mixture was cooled to room temperature and was filteredthrough celite. The filter cake was extracted with ethyl acetate (20mL), and the combined filtrates were concentrated under reducedpressure. The residue was redissolved in toluene (14 mL) and 1,4-dioxane(12 mL), tributylstannane (221 μL, 821 μmol) was added, and theresulting mixture was stirred and heated to 100° C. A solution of2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (8.1 mg, 49 μmol) intoluene (1.6 mL) was added via syringe pump over 30 min. After 20 min,the resulting mixture was cooled to room temperature and wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (0 to 27% ethyl acetate in hexanes)to give 264-1.

Step 2

Example 264 was synthesized in a manner similar to Example 255 using264-1 instead of 255-4. 1H NMR (400 MHz, Acetone-d6) δ 7.78 (d, J=8.5Hz, 1H), 7.39 (s, 1H), 7.29-7.10 (m, 4H), 6.99 (d, J=8.0 Hz, 1H), 6.31(s, 1H), 5.95-5.82 (m, 1H), 5.74 (dd, J=15.3, 7.2 Hz, 1H), 4.91-3.81 (m,12H), 3.74 (d, J=14.2 Hz, 1H), 3.40 (d, J=14.4 Hz, 1H), 3.19 (dd,J=15.3, 9.2 Hz, 1H), 3.09-1.13 (m, 24H), 1.05 (s, 3H). LCMS: 775.1.

Example 265

Example 265 was synthesized in the same manner as Example 250 usingtert-butyl 3-(2-hydroxypropan-2-yl)azetidine-1-carboxylate and Example109. 1H NMR (400 MHz, Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.17 (dd,J=8.6, 2.3 Hz, 1H), 7.14-7.08 (m, 2H), 6.91 (d, J=8.1 Hz, 2H), 5.97 (dt,J=14.2, 6.6 Hz, 1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 4.28 (dd, J=14.8,6.3 Hz, 1H), 4.06 (d, J=2.3 Hz, 2H), 4.03-3.87 (m, 5H), 3.83 (d, J=15.2Hz, 1H), 3.74 (dd, J=9.0, 3.7 Hz, 1H), 3.65 (d, J=14.2 Hz, 1H), 3.24 (d,J=1.5 Hz, 6H), 3.15-2.97 (m, 1H), 2.74 (ddd, J=28.0, 14.0, 7.8 Hz, 3H),2.52-2.40 (m, 2H), 2.34 (q, J=9.0 Hz, 1H), 2.23-2.05 (m, 3H), 2.00-1.85(m, 1H), 1.76 (tt, J=17.1, 9.4 Hz, 2H), 1.43 (t, J=10.4 Hz, 1H), 1.29(s, 2H), 1.13 (d, J=6.4 Hz, 9H). LCMS-ESI+ (m/z): [M+H]⁺ calculated forC₄₀H₅₃ClN₄O₆S: 753.34; found: 752.98.

Example 266

Step 1

Aqueous sodium hydroxide solution (2.0 M, 3.1 mL, 6.2 mmol) was addedvia syringe to a stirred solution of methyl(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylate (500 mg, 1.04 mmol) inmethanol (14.8 mL) at room temperature, and the resulting mixture washeated to 60° C. After 27.5 h, the resulting mixture was allowed to coolto room temperature, acidified by addition of aqueous hydrogen chloridesolution (1.0 M), and concentrated under reduced pressure. The residuewas dissolved in dichloromethane, and the organic layer was washed withwater, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was dissolved in dichloromethane (52 mL),109-2-2 (536 mg, 2.08 mmol) and 4-(dimethylamino)pyridine (423 mg, 3.46mmol) were added, and the resulting mixture was stirred at roomtemperature. 3-(((Ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (498 mg, 2.60 mmol) wasadded. After 18 h, ethyl acetate and aqueous hydrogen chloride solution(1.0 M) were added. The organic layer was washed sequentially with waterand brine, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was dissolved in tetrahydrofuran(2.5 mL), methanol (29 mL), and water (0.16 mL) and the resultingmixture was stirred at room temperature. Potassium carbonate (2.39 g,17.3 mmol) was added, and the resulting mixture was heated to 60° C.After stirring overnight, the resulting mixture was cooled to roomtemperature, and brine (8 mL) and a mixture of citric acid (1.0 g) inwater (10 mL) were added. The aqueous layer was extracted sequentiallywith dichloromethane (30 mL) and ethyl acetate (30 mL). The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (0 to 30% ethyl acetate inhexanes) to give intermediate 266-1.

Step 2

A stirred mixture of intermediate 266-1 (500 mg, 817 μmol) and(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (102 mg, 163 μmol) in 1,2-dichloroethane (272 mL)was heated to 75° C. After 2.5 days, the resulting mixture was allowedto cool to room temperature and was concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel togive intermediate 266-2. ¹H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J=8.5Hz, 1H), 7.50-7.38 (m, 2H), 7.26-7.17 (m, 1H), 7.16-7.06 (m, 1H), 6.93(d, J=8.1 Hz, 1H), 6.52-5.95 (m, 2H), 6.06 (dt, J=14.2, 6.6 Hz, 1H),5.79-5.65 (m, 1H), 4.21 (t, J=5.8 Hz, 1H), 4.13-4.02 (m, 2H), 3.90-3.81(m, 1H), 3.81-3.72 (m, 1H), 3.49-3.25 (m, 2H), 3.07 (dd, J=15.2, 9.1 Hz,1H), 2.92-1.56 (m, 15H), 1.42 (t, J=13.0 Hz, 1H), 1.20 (d, J=6.5 Hz,3H). LCMS: 584.2.

Step 3

A 4-dram vial was charged with intermediate 266-2 (1 equiv, 0.041 mmol,24 mg), diphenyl carbonate (1.3 equiv, 0.053 mmol, 11 mg),N,N-dimethylaminopyridine (2.5 equiv, 0.103 mmol, 13 mg), CH₂Cl₂ (2 mL)and triethylamine (10 equiv, 0.411 mmol, 57 mL), then sealed and stirredat 50° C. for 15 hours. In a separate vial, 3-methoxyazetidinehydrochloride (10 equiv, 0.411 mmol, 51 mg) was treated with CH₂Cl₂ (0.5mL) and triethylamine (20 equiv, 0.822 mmol, 115 mL). The reactionmixtures were then combined and heated to 60° C. overnight. The reactionmixture was concentrated and partially purified by preparative HPLC(10-100% MeCN in water, 0.1% TFA). The fractions containing desiredproduct by LCMS were concentrated, dissolved in EtOAc and washed withwater. The organic layer was back extracted with EtOAc and the combinedorganic layers were dried over sodium sulfate, filtered andconcentrated. The crude material was purified by preparative TLC in 5:1EtOAc:MeOH, filtered across Celite (eluted with 4:1 EtOAc:MeOH) thenconcentrated and purified again by preparative HPLC (10-100% MeCN inwater, 0.1% TFA). The combined clean fractions were lyophilized toafford the desired product Example 266. LCMS-ESI+ (m/z): (M)⁺ calc'd forC₃₆H₄₅ClN₄O₆S: 696.2748; found: 695.92. ¹H NMR (400 MHz, Methanol-d4) δ7.74 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 7.14-7.07 (m, 2H),6.94 (s, 1H), 6.91 (d, J=8.1 Hz, 1H), 5.92 (dt, J=14.0, 6.7 Hz, 1H),5.72 (dd, J=15.2, 8.5 Hz, 1H), 4.28-4.12 (m, 5H), 4.12-4.01 (m, 2H),3.94-3.74 (m, 3H), 3.70-3.53 (m, 2H), 3.37-3.20 (m, 1H), 3.30 (s, 3H),3.06 (dd, J=15.3, 10.0 Hz, 1H), 2.88-2.68 (m, 2H), 2.46-2.24 (m, 3H),2.19-1.78 (m, 8H), 1.72 (q, J=9.0 Hz, 1H), 1.43 (t, J=12.8 Hz, 1H), 1.14(d, J=6.6 Hz, 3H).

Example 267

Example 267 was prepared in the same manner as Example 362 with Example109 and (3-methoxyazetidin-3-yl)methanol hydrochloride. LCMS-ESI+ (m/z):(M)⁺ calc'd for C₃₈H₄₉ClN₄O₇S: 740.3010; found: 739.79. ¹H NMR (400 MHz,Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.6, 2.3 Hz, 1H),7.10 (q, J=3.8 Hz, 2H), 6.94-6.88 (m, 2H), 5.96 (dt, J=14.2, 6.7 Hz,1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 4.30 (dd, J=14.9, 6.2 Hz, 1H),4.12-4.01 (m, 2H), 4.02-3.79 (m, 5H), 3.78-3.71 (m, 3H), 3.69-3.53 (m,2H), 3.33 (s, 3H), 3.30-3.28 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J=15.2,10.3 Hz, 1H), 2.88-2.68 (m, 2H), 2.53-2.40 (m, 2H), 2.38-2.26 (m, 1H),2.22-2.05 (m, 3H), 2.00-1.68 (m, 6H), 1.43 (t, J=12.9 Hz, 1H), 1.13 (d,J=6.6 Hz, 3H).

Example 268

Example 268 was prepared in the same manner as Example 362 with Example109 and 3-(methoxymethyl)azetidin-3-ol trifluoroacetic acid. LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₃₈H₄₉ClN₄O₇S: 741.3083; found: 740.83. ¹H NMR(400 MHz, Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5, 2.4Hz, 1H), 7.13-7.06 (m, 2H), 6.94-6.87 (m, 2H), 5.96 (dt, J=14.3, 6.7 Hz,1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 4.30 (dd, J=14.8, 6.4 Hz, 1H),4.15-3.95 (m, 4H), 3.93-3.70 (m, 4H), 3.70-3.57 (m, 2H), 3.48-3.46 (m,2H), 3.43 (s, 3H), 3.30-3.27 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J=15.2,10.3 Hz, 1H), 2.89-2.68 (m, 2H), 2.52-2.40 (m, 2H), 2.38-2.27 (m, 1H),2.22-2.05 (m, 3H), 2.01-1.67 (m, 6H), 1.42 (t, J=12.9 Hz, 1H), 1.13 (d,J=6.7 Hz, 3H).

Example 269

Example 269 was synthesized in the same manner as Example 18 using4-methoxybenzoic acid and Example 109. ¹H NMR (400 MHz, Methanol-d₄) δ8.18-7.99 (m, 2H), 7.75 (d, J=8.5 Hz, 1H), 7.18 (ddd, J=8.6, 3.6, 2.1Hz, 2H), 7.12 (d, J=2.3 Hz, 1H), 7.04-6.99 (m, 3H), 6.97 (d, J=1.9 Hz,1H), 6.94 (d, J=8.1 Hz, 1H), 6.03 (dt, J=14.3, 6.5 Hz, 1H), 5.60 (dd,J=15.2, 9.0 Hz, 1H), 4.43 (dd, J=14.8, 6.1 Hz, 1H), 4.08 (d, J=1.7 Hz,2H), 3.89 (s, 3H), 3.87-3.82 (m, 2H), 3.78 (dd, J=9.0, 3.6 Hz, 1H), 3.68(d, J=14.2 Hz, 1H), 3.30-3.25 (m, 2H), 3.27 (s, 3H), 3.08 (dd, J=15.3,10.3 Hz, 1H), 2.91-2.70 (m, 2H), 2.48 (td, J=12.7, 5.0 Hz, 2H), 2.39 (q,J=9.0 Hz, 1H), 2.28-2.07 (m, 3H), 2.05-1.70 (m, 5H), 1.44 (t, J=12.7 Hz,1H), 1.16 (d, J=6.4 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₀H₄₆ClN₃O₆S: 732.3; found: 732.2.

Example 270

Example 270 was synthesized in the same manner as Example 237 usingExample 109 and 2-(piperazin-1-yl)acetonitrile. ¹H NMR (400 MHz,Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H),7.12 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8.1, 1.9 Hz, 1H), 6.95 (d, J=8.1 Hz,1H), 6.88 (d, J=2.0 Hz, 1H), 5.95 (dt, J=14.1, 6.7 Hz, 1H), 5.58 (dd,J=15.2, 9.3 Hz, 1H), 4.39 (dd, J=14.9, 6.4 Hz, 1H), 4.09 (s, 2H),3.92-3.80 (m, 1H), 3.80-3.72 (m, 3H), 3.67 (d, J=14.1 Hz, 1H), 3.64-3.55(m, 1H), 3.50 (m, 4H), 3.26 (m, 4H), 3.08 (dd, J=15.2, 10.4 Hz, 1H),2.91-2.71 (m, 3H), 2.61 (s, 4H), 2.47 (dd, J=14.1, 5.3 Hz, 2H), 2.33 (q,J=9.2 Hz, 1H), 2.20 (q, J=7.6 Hz, 1H), 2.16-2.04 (m, 3H), 2.04-1.85 (m,1H), 1.77 (m, 3H), 1.45 (t, J=12.8 Hz, 1H), 1.15 (d, J=6.6 Hz, 3H).LCMS-ESI+: calc'd for C₃₉H₅₀ClN₆O₅S: 749.32 (M+H); found: 749.26 (M+H).

Example 271

Example 271 was synthesized in a manner similar to Example 106 using2,4-dimethoxypyrimidine-5-carboxylic acid instead of2-((tetrahydro-2H-pyran-4-yl)oxy) acetic acid. 1H NMR (400 MHz,Acetone-d6) δ 9.00 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.54-7.47 (m, 1H),7.34 (d, J=1.9 Hz, 1H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.14 (d, J=2.3 Hz,1H), 6.94 (d, J=8.2 Hz, 1H), 6.18 (dt, J=14.2, 6.6 Hz, 1H), 5.67 (dd,J=15.6, 7.4 Hz, 1H), 4.27 (s, 3H), 4.13 (d, J=12.1 Hz, 1H), 4.09 (s,3H), 4.04 (d, J=12.1 Hz, 1H), 4.02-3.72 (m, 4H), 3.49 (d, J=14.4 Hz,1H), 3.26 (s, 3H), 3.16 (dd, J=15.1, 11.0 Hz, 1H), 2.97-1.37 (m, 16H),1.14 (d, J=6.9 Hz, 3H). LCMS: 764.1.

Example 272

Example 272 was synthesized in the same manner as Example 237 usingExample 109 and 7-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-onehydrochloride. ¹H NMR (400 MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H),7.19 (dd, J=8.5, 2.3 Hz, 1H), 7.14-7.07 (m, 2H), 6.94 (d, J=8.1 Hz, 1H),6.90 (d, J=2.0 Hz, 1H), 5.96 (dt, J=14.3, 6.7 Hz, 1H), 5.58 (dd, J=15.1,9.2 Hz, 1H), 4.43-4.15 (m, 6H), 4.09 (d, J=1.6 Hz, 2H), 3.84 (d, J=7.0Hz, 3H), 3.76 (dd, J=9.2, 3.6 Hz, 1H), 3.67 (d, J=14.2 Hz, 1H), 3.26 (m,4H), 3.08 (dd, J=15.3, 10.3 Hz, 1H), 2.88 (s, 3H), 2.84-2.72 (m, 2H),2.55-2.42 (m, 3H), 2.33 (m, 1H), 2.27-2.06 (m, 3H), 1.94 (t, J=6.9 Hz,2H), 1.78 (m, 3H), 1.45 (t, J=12.7 Hz, 1H), 1.15 (d, J=6.6 Hz, 3H).LCMS-ESI+: calc'd for C₃₉H₄₉ClN₅O₇S: 766.30 (M+H); found: 766.10 (M+H).

Example 273

Example 273 was synthesized in the same manner as Example 18 using2-methoxypyrimidine-5-carboxylic acid and Example 109. ¹H NMR (400 MHz,Chloroform-d) δ 9.21 (d, J=5.1 Hz, 2H), 7.70 (d, J=8.5 Hz, 1H), 7.19(dd, J=8.5, 2.4 Hz, 1H), 7.09 (s, 2H), 6.99 (dd, J=8.4, 3.8 Hz, 1H),6.92 (d, J=9.4 Hz, 1H), 5.94-5.85 (m, 1H), 5.53 (dd, J=15.2, 9.1 Hz,1H), 5.37 (s, 1H), 4.69 (d, J=14.9 Hz, 1H), 4.14 (d, J=1.5 Hz, 4H), 4.09(s, 3H), 3.83 (d, J=15.3 Hz, 1H), 3.75-3.66 (m, 2H), 3.24 (s, 2H), 3.12(s, 1H), 2.98 (dd, J=15.3, 10.3 Hz, 1H), 2.78 (dd, J=16.4, 11.7 Hz, 3H),2.53-2.18 (m, 2H), 2.16-1.99 (m, 1H), 1.95 (d, J=10.5 Hz, 2H), 1.85-1.77(m, 2H), 1.63 (t, J=9.5 Hz, 1H), 1.39 (t, J=12.7 Hz, 1H), 1.27-1.19 (m,1H), 1.15 (d, J=6.1 Hz, 1H), 1.08 (d, J=6.1 Hz, 3H). LCMS-ESI+ (m/z):calcd for H+C₃₈H₄₄ClN₅O₆S: 733.27; found: 734.050 (M+H).

Example 274

A 2-dram vial was charged with Example 267 (1 equiv, 0.013 mmol, 10 mg)and THF (0.5 mL). Sodium hydride (60% dispersion in oil, 2 equiv, 0.027mmol, 1.1 mg) was added and the reaction mixture stirred for 10 minutes.Iodomethane (5 equiv, 0.067 mmol, 4.2 mL) was then added and thereaction mixture was stirred for an additional 30 minutes at which pointit was quenched with methanol, concentrated then re-dissolved inmethanol, and purified by preparative HPLC (60-100% MeCN in water, 0.1%TFA). The combined clean fractions were lyophilized to afford thedesired product Example 274. LCMS-ESI+ (m/z): (M)⁺ calc'd forC₃₉H₅₁ClN₄O₇S: 754.3167; found: 754.07. ¹H NMR (400 MHz, Methanol-d4) δ7.73 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5, 2.4 Hz, 1H), 7.10 (td, J=3.9,1.9 Hz, 2H), 6.96-6.88 (m, 2H), 5.96 (dt, J=14.2, 6.7 Hz, 1H), 5.56 (dd,J=15.2, 9.1 Hz, 1H), 4.30 (dd, J=14.9, 6.3 Hz, 1H), 4.13-4.02 (m, 2H),4.01-3.78 (m, 5H), 3.74 (dd, J=9.2, 3.7 Hz, 1H), 3.69-3.54 (m, 4H), 3.42(s, 3H), 3.32 (s, 3H), 3.31-3.28 (m, 1H), 3.24 (s, 3H), 3.06 (dd,J=15.2, 10.3 Hz, 1H), 2.87-2.69 (m, 2H), 2.54-2.40 (m, 2H), 2.32 (p,J=9.0 Hz, 1H), 2.23-2.05 (m, 3H), 2.00-1.66 (m, 6H), 1.43 (t, J=12.8 Hz,1H), 1.13 (d, J=6.7 Hz, 3H).

Example 275

Example 275 was synthesized in the same manner as Example 362, usingExample 109 and 4-(azetidin-3-yloxy)pyridine dihydrochloride. LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₄₁H₄₈ClN₅O₆S: 774.3087; found: 773.81. ¹H NMR(400 MHz, Methanol-d4) δ 8.69 (d, J=7.4 Hz, 2H), 7.72 (d, J=8.5 Hz, 1H),7.53-7.43 (m, 2H), 7.17 (dd, J=8.5, 2.4 Hz, 1H), 7.13-7.05 (m, 2H),6.96-6.86 (m, 2H), 5.96 (dt, J=14.3, 6.8 Hz, 1H), 5.56 (dd, J=15.2, 9.1Hz, 1H), 5.39 (tt, J=6.6, 3.5 Hz, 1H), 4.56 (s, 2H), 4.32 (dd, J=14.9,6.4 Hz, 1H), 4.26-3.96 (m, 4H), 3.83 (d, J=15.1 Hz, 1H), 3.74 (dd,J=9.2, 3.7 Hz, 1H), 3.70-3.55 (m, 2H), 3.30-3.27 (m, 1H), 3.24 (s, 3H),3.06 (dd, J=15.3, 10.3 Hz, 1H), 2.89-2.69 (m, 2H), 2.53-2.39 (m, 2H),2.32 (q, J=9.0 Hz, 1H), 2.23-2.06 (m, 3H), 2.01-1.66 (m, 6H), 1.43 (t,J=12.6 Hz, 1H), 1.13 (d, J=6.6 Hz, 3H).

Example 276

Example 276 was synthesized in the same manner as Example 237 usingExample 109 and 2-(3-methoxyazetidin-3-yl)-1-methyl-1H-imidazoledihydrochloride. ¹H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H),7.63 (d, J=1.9 Hz, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.19 (dd, J=8.5, 2.3 Hz,1H), 7.12 (d, J=2.3 Hz, 1H), 7.08 (dd, J=8.1, 1.8 Hz, 1H), 6.94 (d,J=8.1 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 5.97 (dt, J=14.3, 6.6 Hz, 1H),5.58 (dd, J=15.2, 9.2 Hz, 1H), 4.59 (s, 2H), 4.49-4.28 (m, 3H), 4.09 (d,J=1.7 Hz, 2H), 3.88 (s, 3H), 3.76 (dd, J=9.2, 3.7 Hz, 1H), 3.73-3.62 (m,1H), 3.26 (m, 4H), 3.21 (s, 3H), 3.14-3.05 (m, 1H), 2.87-2.63 (m, 2H),2.48 (m, 3H), 2.33 (t, J=9.1 Hz, 1H), 2.27-2.08 (m, 3H), 2.07-1.86 (m,3H), 1.79 (tt, J=17.4, 9.5 Hz, 3H), 1.45 (t, J=12.7 Hz, 1H), 1.15 (d,J=6.5 Hz, 3H). LCMS-ESI+: calc'd for C₄₁H₅₂ClN₆O₆S: 791.33 (M+H); found:791.43 (M+H).

Example 277

Example 277 was synthesized in the same manner as Example 237 usingExample 109 and 5-(3-methoxyazetidin-3-yl)-1-methyl-1H-1,2,4-triazoledihydrochloride. ¹H NMR (400 MHz, Methanol-d4) δ 7.94 (s, 1H), 7.75 (d,J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.3 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H),7.09 (d, J=8.4 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H),5.96 (dt, J=14.2, 6.6 Hz, 1H), 5.58 (dd, J=15.2, 9.2 Hz, 1H), 4.56 (m,4H), 4.34 (dd, J=14.8, 6.3 Hz, 1H), 4.08 (d, J=1.5 Hz, 2H), 3.91 (s,3H), 3.85 (d, J=15.1 Hz, 1H), 3.76 (dd, J=9.3, 3.7 Hz, 1H), 3.67 (d,J=14.2 Hz, 1H), 3.59 (d, J=14.0 Hz, 1H), 3.26 (m, 4H), 3.13 (s, 3H),3.11-3.01 (m, 1H), 2.89-2.70 (m, 2H), 2.56-2.42 (m, 3H), 2.34 (q, J=9.2Hz, 1H), 2.24-2.05 (m, 4H), 2.05-1.86 (m, 1H), 1.78 (m, 3H), 1.45 (t,J=12.6 Hz, 1H), 1.15 (d, J=6.3 Hz, 3H). LCMS-ESI+: calc'd forC₄₁H₅₂ClN₆O₆S: 792.32 (M+H); found: 792.25 (M+H).

Example 278

Example 278 was synthesized in a manner similar to Example 106 using3,6-dimethoxypyridazine-4-carboxylic acid instead of2-((tetrahydro-2H-pyran-4-yl)oxy) acetic acid. 1H NMR (400 MHz,Acetone-d6) δ 7.78 (d, J=8.5 Hz, 1H), 7.52 (s, 1H), 7.38 (d, J=8.0 Hz,1H), 7.29-7.20 (m, 2H), 7.14 (d, J=2.4 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H),6.23-6.08 (m, 1H), 5.65 (dd, J=15.3, 7.9 Hz, 1H), 4.22 (s, 3H), 4.13 (d,J=12.1 Hz, 1H), 4.08 (s, 3H), 4.07-3.57 (m, 5H), 3.45 (d, J=14.4 Hz,1H), 3.25 (s, 3H), 3.16 (dd, J=15.2, 10.5 Hz, 1H), 2.95-1.54 (m, 15H),1.53-1.43 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). LCMS: 764.2.

Example 279

Example 154 (500 mg, 0.68 mmol) was combined with selenium dioxide (377mg, 5 equiv.) and 1,4-dioxane (7 mL) was added. The reaction mixture washeated to reflux and the progress of the reaction was monitored by LCMS.After 4 hours (approximately 50% conversion), the reaction was cooled toroom temperature and concentrated under reduced pressure. The residuewas purified by Gilson reverse phase prep HPLC (50-100% ACN/H₂O with0.1% TFA) to give Example 279. ¹H NMR (400 MHz, Methanol-d₄) δ 8.15 (s,1H), 7.72 (d, J=9A Hz, 1H), 7.37 (dd, J=8.3, 1.8 Hz, 1H), 7.19 (s, 1H),7.16-7.07 (m, 2H), 6.89 (d, J=8.2 Hz, 1H), 6.15 (dd, J=15.5, 5.3 Hz,1H), 5.83 (ddd, J=15.5, 8.0, 1.5 Hz, 1H), 4.54 (s, 1H), 4.05 (m, 7H),3.90-3.82 (m, 3H), 3.81 (s, 3H), 3.69 (d, J=14.3 Hz, 1H), 3.41 (d,J=14.4 Hz, 1H), 3.29 (s, 3H), 3.18-3.04 (m, 1H), 2.92-2.69 (m, 2H), 2.51(br, 2H), 2.44-2.25 (m, 1H), 2.16-2.03 (m, 1H), 2.02-1.92 (m, 3H),1.88-1.74 (m, 3H), 1.43 (t, J=11.9 Hz, 1H), 1.15 (d, J=6.9 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₆ClN₅O₇S: 752.3; found: 751.9.

Example 280

Example 223 (10 mg, 0.014 mmol) was combined with PtO₂ (15 mg, 0.028mmol) and ethanol (0.5 mL) was added. A hydrogen balloon (1 atm) fittedto a glass adapter was attached to the round bottom flask. The reactionwas stirred under atmospheric hydrogen for 5 hours and the progress ofthe reaction was monitored by LCMS. Upon completion, the reaction vesselwas purged with a stream of argon. The solids were filtered away andwashed with additional ethanol. The reaction mixture was thenconcentrated under reduced pressure and the residue was purified byGilson reverse phase prep HPLC (50-100% ACN/H₂O with 0.1% TFA) to giveExample 280. ¹H NMR (400 MHz, Methanol-d₄) δ 8.08 (s, 1H), 7.77 (d,J=8.5 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.28 (s, 1H), 7.18 (dd, J=8.5,2.3 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.15-4.01(m, 5H), 4.01-3.84 (m, 3H), 3.81 (s, 3H), 3.78-3.68 (m, 2H), 3.19-3.07(m, 1H), 2.89-2.76 (m, 2H), 2.58-2.21 (m, 3H), 2.12 (d, J=13.4 Hz, 1H),2.01-1.92 (m, 4H), 1.88-1.41 (m, 11H), 1.10 (d, J=6.6 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₇H₄₆ClN₅O₆S: 724.3; found: 724.1.

Example 281 and Example 282

Step 1

To well stirred solution of methyl (1S,2R)-2-(2-hydroxy ethyl)cyclopropane-1-carboxylate (0.5 g, 3.46 mmol) in DCM (23 mL) at 0° C.under argon was added Dess Martin periodinane (1.76 g, 4.16 mmol) atonce, warmed to room temperature (20 min), and stirred for 2 h. Thereaction was cooled to 0° C., and quenched with 1:1 mixture of 1 Naqueous solution of Na₂S₂O₃ and saturated NaHCO₃ (40 mL). The aqueoussolution was extracted with DCM (2×20 mL). Combined DCM solution wasadded another 1:1 mixture of 1 N aqueous solution of Na₂SO₂O₃ andsaturated NaHCO₃ (20 mL). The DCM layers were combined and washed withbrine solution once, dried over Na₂SO₄, concentrated and used for nextstep.

Step 2

To a solution of methyl (1S,2R)-2-(2-oxoethyl)cyclopropane-1-carboxylatein DCM (17.5 mL) at −78° C. was added diethylaminosulfur trifluoride(DAST) (1.7 g, 10.55 mmol) dropwise and cooling bath was removed. Themixture was stirred at room temperature overnight. The reaction wasquenched with Na₂HCO₃, partitioned with water and DCM. The aqueoussolution was extracted with DCM (2×20 mL). The combined DCM solution wasdried over Na₂SO₄, filtered, concentrated and used for next step.

Step 3

To the crude methyl(1S,2R)-2-(2,2-difluoroethyl)cyclopropane-1-carboxylate (300 mg, 1.82mmol) were added THF (15 mL), MeOH (3 mL) and 1 N LiOH (3 mL). Thismixture was stirred at 65° C. for 90 min. The reaction was cooled toroom temperature, and solvent was removed under reduced pressure. Thecrude residue was dissolved in water (20 mL), and acidified with 1.5 NHCl by drop wise addition to maintain pH 2-3 and stirred for 5 min. Aprecipitate was formed, filtered, washed with water, and dried toprovide the crude product(1S,2R)-2-(2,2-difluoroethyl)cyclopropane-1-carboxylic acid used fornext step. ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H), 6.09 (tt, J=56.5,4.5 Hz, 1H), 1.84 (tdd, J=17.5, 7.2, 4.5 Hz, 2H), 1.43 (ddt, J=13.1,9.8, 7.3 Hz, 2H), 0.97 (dt, J=8.8, 4.3 Hz, 1H), 0.77 (dddd, J=17.6, 8.1,6.2, 3.9 Hz, 1H).

Step 4

To the mixture of trans-2-(2,2-difluoroethyl)cyclopropane-1-carboxylicacid (40 mg, 0.26 mmol) in acetonitrile (2 mL) were added triethylamine(118 uL, 0.84 mmol) and diphenyl phosphoryl azide (73.6 mg, 0.26 mmol).The mixture was then heated at 60° C. for 2 h. The reaction mixture wascooled to room temperature. To this mixture was added Example 109 atonce and stirred at 60° C. 24 h. The reaction was concentrated,dissolved in MeOH (3 mL), filtered and purified by reverse phase prepHPLC, eluted with 60-100% ACN/H₂O with 0.1% TFA to afford two isomersExample 281 and Example 282 and the stereochemistry is arbitrarilyassigned.

Example 281

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.1Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.98-6.91 (m,1H), 6.84 (dd, J=8.2, 4.9 Hz, 1H), 6.15-5.87 (m, 2H), 5.61 (dt, J=15.6,8.8 Hz, 1H), 4.18 (td, J=16.0, 6.9 Hz, 2H), 3.99 (d, J=5.9 Hz, 2H),3.87-3.70 (m, 4H), 3.63 (d, J=14.3 Hz, 1H), 3.27 (d, J=4.1 Hz, 4H), 3.05(dd, J=15.2, 9.8 Hz, 1H), 2.90-2.64 (m, 2H), 2.49 (d, J=38.4 Hz, 4H),2.31-1.63 (m, 5H), 1.52-1.22 (m, 3H), 1.12 (d, J=6.6 Hz, 4H), 0.96 (d,J=7.7 Hz, 1H), 0.83 (dt, J=9.5, 4.8 Hz, 1H), 0.70 (q, J=6.2 Hz, 1H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₇ClF₂N₄O₅S: 745.29; found:744.75.

Example 282

¹H NMR (400 MHz, Methanol-d₄) δ 7.78-7.52 (m, 1H), 7.40-7.10 (m, 1H),7.10-6.91 (m, 2H), 6.85 (d, J=8.0 Hz, 1H), 6.22-5.76 (m, 1H), 5.67-5.51(m, 1H), 4.16 (ddd, J=25.1, 15.0, 8.3 Hz, 1H), 4.00 (s, 2H), 3.90-3.70(m, 2H), 3.63 (d, J=14.2 Hz, 1H), 3.27 (d, J=3.1 Hz, 3H), 3.15-2.94 (m,1H), 2.90-2.62 (m, 2H), 2.61-1.63 (m, 15H), 1.33 (d, J=39.5 Hz, 3H),1.12 (t, J=6.3 Hz, 3H), 0.98 (d, J=6.8 Hz, 1H), 0.90-0.77 (m, 1H), 0.69(q, J=6.3 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₈H₄₇ClF₂N₄O₅S:745.29; found: 744.76.

Example 283

Example 279 (200 mg, 0.27 mmol) was dissolved in DMF (2.7 mL) and sodiumhydride (60% dispersion in oil, 22 mg, 0.53 mmol, 2 equiv.) was added inone portion. The mixture was stirred at room temperature for 5 minbefore iodomethane (76 mg, 0.53 mmol, 2 equiv.) was added. The reactionwas then heated to 50° C. and the progress of the reaction was monitoredby LCMS. Upon observing significant conversion (approx. 4:1 product:starting material), the reaction was cooled to 0° C. and water was added(ca. 5 drops). The residue was then purified directly by Gilson reversephase prep HPLC (60-100% ACN/H₂O with 0.1% TFA) to give Example 283. ¹HNMR (400 MHz, Methanol-d₄) δ 8.08 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.36(d, J=7.9 Hz, 1H), 7.24-7.15 (m, 2H), 7.12 (d, J=2.3 Hz, 1H), 6.92 (d,J=8.2 Hz, 1H), 6.01 (dd, J=15.4, 7.8 Hz, 1H), 5.83 (dd, J=15.3, 8.6 Hz,1H), 4.06 (m, 6H), 3.9-3.8 (m, 7H), 3.73 (d, J=14.5 Hz, 1H), 3.41 (d,J=14.4 Hz, 1H), 3.31 (s, 3H), 3.30 (s, 3H), 3.19-3.06 (m, 1H), 2.92-2.70(m, 2H), 2.52 (br, 2H), 2.24 (m, 1H), 2.05 (m, 2H), 1.96 (m, 3H), 1.83(m, 3H), 1.46 (m, 1H), 1.19 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₉H₄₈ClN₅O₇S: 766.3; found: 766.0.

Example 284

Step 1

Synthesis of methyl5-[[(3R)-4-isopropyl-3-methyl-piperazin-1-yl]methyl]-1-methyl-pyrrole-3-carboxylatebisTFA salt: The mixture of methyl 5-formyl-1-methyl-pyrrole-3-carboxylate(50.0 mg, 0.299 mmol) and (2R)-1-isopropyl-2-methyl-piperazine (42.5 mg,0.299 mmol) in DCE (0.5 mL) was stirred at room temperature for 10minutes before sodium triacetoxyborohydride (95.1 mg, 0.449 mmol) wasadded. The resulting mixture was stirred for overnight. The reaction wasconcentrated, redissolved in a mixture of water:DMF (5:1 V:V), filteredand purified by Gilson reverse phase prep HPLC, eluted with 2-50%ACN/H₂O with 0.1% TFA. The desired fractions were combined and frozendried to give methyl5-[[(3R)-4-isopropyl-3-methyl-piperazin-1-yl]methyl]-1-methyl-pyrrole-3-carboxylate;2,2,2-trifluoroacetic acid (60.0 mg). LCMS-ESI+ (m/z): calcd H+ forC₁₆H₂₇N₃O₂:294.21; found: 293.99.

Step 2

Synthesis of5-[[(3R)-4-isopropyl-3-methyl-piperazin-1-yl]methyl]-1-methyl-pyrrole-3-carboxylicacid; bis TFA salt: methyl5-[[(3R)-4-isopropyl-3-methyl-piperazin-1-yl]methyl]-1-methyl-pyrrole-3-carboxylate;bis TFA salt (60.0 mg, 0.115 mmol) was dissolved in a mixture of MeOH(1.0 mL) and THF (1.0 mL) at rt. 1N NaOH (1.15 mL, 1.15 mmol) was added.The resulting mixture was then heated to 50° C. for 8 hrs. The reactionwas concentrated, redissolved in a solution of 1N HCl (1.0 mL), filteredand purified by reverse phase prep HPLC, eluted with 2-50% ACN/H₂O with0.1% TFA. Desired fractions were combined and frozen dried to give thetitle compound. LCMS-ESI+ (m/z): calcd H+ for C₁₅H25N₃O₂:280.19; found:280.20.

Step 3: Synthesis of Example 284

the same procedure was followed as Example 18 using Example 109 andIntermediate 284-2. 1H NMR (400 MHz, Methanol-d4) δ 7.70 (d, J=8.4 Hz,1H), 7.60 (d, J=1.8 Hz, 1H), 7.32 (dd, J=8.2, 1.8 Hz, 1H), 7.12-7.03 (m,3H), 6.88 (d, J=8.3 Hz, 1H), 6.62-6.57 (m, 1H), 6.20-6.07 (m, 1H), 5.64(dd, J=15.4, 8.4 Hz, 1H), 4.19 (dd, J=14.8, 6.4 Hz, 1H), 4.08-3.92 (m,4H), 3.87-3.77 (m, 2H), 3.75 (s, 3H), 3.68 (d, J=14.3 Hz, 1H), 3.64-3.54(m, 2H), 3.49-3.42 (m, 1H), 3.39 (d, J=14.3 Hz, 1H), 3.30 (s, 3H),3.18-3.04 (m, 4H), 2.89-2.70 (m, 2H), 2.67-2.58 (m, 1H), 2.53-2.33 (m,3H), 2.33-2.17 (m, 3H), 2.15-2.06 (m, 1H), 2.04-1.91 (m, 3H), 1.86-1.73(m, 3H), 1.46-1.34 (m, 8H), 1.29 (d, J=6.6 Hz, 3H), 1.15 (d, J=6.4 Hz,3H). LCMS-ESI+ (m/z): calcd H+ for C₄₇H₆₃ClN₆O₅S: 859.43; found: 859.13.

Example 285

Step 1

Synthesis of tert-butyl(3S)-4-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-3-methyl-piperazine-1-carboxylate:To the mixture of tert-butyl (3R)-3-methylpiperazine-1-carboxylate (250mg, 1.25 mmol) and (2R)-2-(methoxycarbonyl amino)-3-methyl-butanoic acid(241 mg, 1.37 mmol) in DCM (6.0 mL) at room temperature was addedEDCI.HCl (358 mg, 1.87 mmol) followed by DMAP (229 mg, 1.87 mmol). Theresulting mixture was stirred at room temperature for overnight beforeit was diluted with DCM. The organic layer was washed sequentially withsat. NH₄Cl, sat. NaHCO₃ and brine, then it was dried over sodiumsulfate, filtered and concentrated to give crude product which waspurified by combiflash (0-100% EtOAc/hexanes). Desired fractions werecombined and concentrated to give desired product (446 mg). LCMS-ESI+(m/z): calcd H+ for C₁₇H₃₁N₃O₅: 358.23; found: 358.20.

Step 2

Synthesis of methylN-[(1S)-2-methyl-1-[(2S)-2-methylpiperazine-1-carbonyl]propyl]carbamate;di HCl salt: tert-butyl (3S)-4-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-3-methyl-piperazine-1-carboxylate (446 mg,1.25 mmol) from step 1 was then dissolved in DCM (3.0 mL) and treatedwith 4 N HCl in 1,4-dioxane (1.25 mL) at room temperature for 3 hrs. Thereaction was concentrated, coevaporated with EtOAc (3×4.0 mL) to givethe title compound (270 mg). LCMS-ESI+ (m/z): calcd H+ for C₁₂H₂₃N₃O₃:258.17; found: 258.17.

Step 3: Synthesis of Example 285

the same procedure was followed as the synthesis of Example 75 usingExample 109, Intermediate 285-2 and DIEA. 1H NMR (400 MHz, Methanol-d4)δ 7.74 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.14-7.05 (m,2H), 6.95 (d, J=8.1 Hz, 1H), 6.88 (d, J=1.9 Hz, 1H), 6.00-5.90 (m, 1H),5.58 (dd, J=15.2, 9.3 Hz, 1H), 4.47-4.31 (m, 3H), 4.13-4.04 (m, 2H),3.85 (d, J=15.1 Hz, 1H), 3.76 (dd, J=9.3, 3.7 Hz, 1H), 3.71-3.62 (m,5H), 3.31-3.24 (m, 5H), 3.12-3.04 (m, 2H), 2.88-2.70 (m, 2H), 2.54-2.41(m, 2H), 2.38-2.24 (m, 1H), 2.23-1.67 (m, 12H), 1.49-1.30 (m, 3H),1.23-1.08 (m, 5H), 1.03-0.89 (m, 7H). LCMS-ESI+ (m/z): calcd H+ forC₄₅H₆₁ClN₆O₈S: 881.40; found: 880.97.

Example 286

Example 286 was synthesized in the same manner as Example 182, using1-(azetidin-3-yl)-3-methoxy-azetidine instead ofrac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropan-1-amine. 1H NMR (400MHz, Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 7.11(dd, J=9.6, 1.9 Hz, 2H), 6.96-6.87 (m, 2H), 6.02 (dt, J=14.2, 6.6 Hz,1H), 5.56 (dd, J=15.2, 9.2 Hz, 1H), 4.45 (s, 1H), 4.34 (q, J=8.4, 7.5Hz, 4H), 4.28 (s, 1H), 4.12 (d, J=13.1 Hz, 2H), 4.07 (d, J=1.9 Hz, 2H),4.02 (d, J=15.2 Hz, 2H), 3.86 (d, J=15.2 Hz, 1H), 3.77 (dd, J=9.2, 3.7Hz, 1H), 3.66 (d, J=14.0 Hz, 2H), 3.39 (s, 3H), 3.26 (s, 4H), 3.07 (dd,J=15.3, 10.2 Hz, 1H), 2.89-2.69 (m, 2H), 2.55-2.41 (m, 2H), 2.41-2.24(m, 1H), 2.18 (t, J=7.5 Hz, 1H), 2.09 (t, J=14.3 Hz, 3H), 2.03-1.87 (m,3H), 1.78 (tt, J=17.7, 9.5 Hz, 3H), 1.44 (t, J=12.8 Hz, 1H), 1.12 (d,J=6.5 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₅₂ClN₅O₆S: 766.33;found: 766.11.

Example 287

Example 286 was synthesized in the same manner as Example 182, using1-(azetidin-3-yl)-4-methoxy-piperidine instead ofrac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropan-1-amine. 1H NMR (400MHz, Methanol-d4) δ 7.73 (d, J=8.5 Hz, 1H), 7.24-7.06 (m, 3H), 6.90 (d,J=7.2 Hz, 2H), 6.00 (dd, J=14.7, 7.6 Hz, 1H), 5.57 (dd, J=15.2, 9.2 Hz,1H), 4.34 (dd, J=14.6, 6.7 Hz, 3H), 4.21 (s, 2H), 4.07 (d, J=1.9 Hz,3H), 3.93-3.55 (m, 6H), 3.40 (s, 3H), 3.26 (s, 3H), 3.08 (dd, J=15.3,10.3 Hz, 3H), 2.90-2.70 (m, 3H), 2.58-2.42 (m, 3H), 2.34 (t, J=9.5 Hz,2H), 2.15 (dd, J=25.4, 10.7 Hz, 4H), 2.04-1.60 (m, 8H), 1.44 (t, J=12.7Hz, 1H), 1.13 (d, J=6.5 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₂H₅₆ClN₅O₆S: 794.36; found: 794.05.

Example 288

Example 288 was synthesized in the same manner as Example 283 using2-fluoropyrazine and Example 279. ¹H NMR (400 MHz, Methanol-d₄) δ 8.25(d, J=1.4 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.95 (dd,J=2.8, 1.4 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.43 (dd, J=8.3, 1.8 Hz,1H), 7.25 (s, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 6.91(d, J=8.3 Hz, 1H), 6.24 (dd, J=15.6, 5.4 Hz, 1H), 6.15 (s, 1H), 5.88(dd, J=15.5, 8.1 Hz, 1H), 4.24 (t, J=5.8 Hz, 2H), 4.06 (d, J=6.0 Hz,5H), 3.81 (m, 6H), 3.72 (d, J=14.4 Hz, 1H), 3.40 (d, J=14.4 Hz, 1H),3.16 (s, 3H), 3.08 (dd, J=15.2, 10.4 Hz, 1H), 2.91-2.61 (m, 3H), 2.49(dd, J=27.4, 14.6 Hz, 2H), 2.10 (d, J=13.7 Hz, 1H), 2.03-1.81 (m, 2H),1.73 (dq, J=15.0, 8.1, 7.7 Hz, 2H), 1.59-1.39 (m, 2H), 1.22 (d, J=6.9Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₂H₄₈ClN₇O₇S: 830.3; found:829.7.

Example 289

Example 289 was synthesized in the similar methods described herein.LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₃₆H₄₅ClN₄O₆S: 697.2821; found:696.81.

Example 290

Synthesis of Intermediate 290-1: Intermediate 359-4 (35.0 mg, 0.0585mmol) was dissolved in EtOH (10.0 mL) at room temperature, PtO₂ (16.0mg) was added, the resulting mixture was degassed and hydrogenated underhydrogen balloon for 1 hr. The reaction was then filtered through 0.45μm PTFE disc filter. The filtrate was concentrated, redissolved in DMF(1.2 mL), filtered, and purified by reverse phase prep HPLC. Desiredfractions were combined and frozen dried to give 359-4. 1H NMR (400 MHz,Methanol-d4) δ 7.78 (d, J=8.5 Hz, 1H), 7.41 (dd, J=8.2, 1.9 Hz, 1H),7.23-7.14 (m, 2H), 7.11 (d, J=2.3 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H),4.11-3.97 (m, 3H), 3.86 (d, J=15.0 Hz, 1H), 3.80-3.72 (m, 1H), 3.69-3.62(m, 1H), 3.28 (d, J=14.1 Hz, 1H), 3.05 (dd, J=15.2, 9.2 Hz, 1H),2.86-2.69 (m, 2H), 2.50-2.31 (m, 2H), 2.31-2.22 (m, 1H), 2.13-2.05 (m,1H), 2.01-1.84 (m, 3H), 1.83-1.74 (m, 2H), 1.74-1.52 (m, 4H), 1.51-1.23(m, 7H), 1.04 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ forC₃₂H₄₂ClN₃O₄: 600.26; found: 600.14.

Synthesis of Example 290

Intermediate 290-2 (10.0 mg, 0.0137 mmol) and3-methoxy-1-methyl-pyrazole-4-carboxylic acid (2.79 mg, 0.0179 mmol) wasmixed in DCM (1.0 mL) at room temperature. To this stirred mixture wasadded EDCI.HCl (3.41 mg, 0.0179 mmol) and DMAP (2.18 mg, 0.0179 mmol)followed by DIEA (5.32 mg, 0.041 mmol). The newly formed mixture wasstirred at room temperature for 2 days and then it was concentrated,redissolved in DMF (1.2 mL), filtered and purified by reverse phase prepHPLC. 1H NMR (400 MHz, Methanol-d4) δ 7.95 (s, 1H), 7.77 (d, J=8.5 Hz,1H), 7.31-7.24 (m, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.16-7.10 (m, 2H),6.95 (d, J=8.2 Hz, 1H), 4.19-4.06 (m, 3H), 3.99 (s, 3H), 3.85 (d, J=15.0Hz, 1H), 3.79 (s, 3H), 3.74-3.65 (m, 2H), 3.18-3.08 (m, 1H), 2.88-2.71(m, 2H), 2.51-2.20 (m, 3H), 2.15-2.06 (m, 1H), 2.04-1.87 (m, 3H),1.87-1.77 (m, 2H), 1.77-1.33 (m, 12H), 1.14 (d, J=6.8 Hz, 3H). LCMS-ESI+(m/z): calcd H+ for C₃₈H₄₈ClN₅O₆S: 738.30; found: 737.88.

Example 291

Example 291 was synthesized in the same manner as Example 283 using1-iodo-2-methoxyethane and Example 279. ¹H NMR (400 MHz, Methanol-d₄) δ8.09 (s, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.23-7.15(m, 2H), 7.12 (d, J=2.3 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.04 (dd,J=15.4, 7.2 Hz, 1H), 5.84 (dd, J=15.5, 8.5 Hz, 1H), 4.08 (m, 8H), 3.82(m, 5H), 3.76-3.64 (m, 2H), 3.58-3.38 (m, 4H), 3.34 (s, 3H), 3.30 (s,3H), 3.19-3.06 (m, 2H), 2.91-2.71 (m, 2H), 2.51 (m, 2H), 2.26 (m, 1H),2.12 (m, 1H), 1.96 (m, 2H), 1.82 (d, J=6.3 Hz, 3H), 1.46 (t, J=13.1 Hz,1H), 1.20 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₁H₅₁ClFN₅O₈S: 810.3; found: 810.0.

Example 292

Example 292 was synthesized in the same manner as Example 75 usingazetidin-3-yl-dimethylcarbamate bis-hydrochloric acid (prepared in samemanner as trans-3-aminocyclobutyl dimethylcarbamate bis-hydrochloricacid (Example 360-step 1/2) starting from tert-butyl3-hydroxyazetidine-1-carboxylate instead oftrans-3-((tert-butoxycarbonyl)amino)cyclobutyl dimethylcarbamate) andExample 109. ¹H NMR (400 MHz, Methanol-d4) δ 7.72 (d, J=8.5 Hz, 1H),7.16 (d, J=8.8 Hz, 1H), 7.12-7.05 (m, 2H), 6.95-6.86 (m, 2H), 5.96 (dq,J=14.1, 7.2 Hz, 1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 5.15-5.00 (m, 1H),4.30 (dd, J=15.5, 6.9 Hz, 4H), 4.13-3.90 (m, 4H), 3.83 (d, J=15.2 Hz,1H), 3.74 (dd, J=9.1, 3.6 Hz, 1H), 3.69-3.54 (m, 2H), 3.24 (s, 3H), 3.06(dd, J=15.3, 10.3 Hz, 1H), 2.98 (s, 3H), 2.90 (s, 3H), 2.87-2.68 (m,2H), 2.44 (dd, J=14.2, 6.7 Hz, 2H), 2.39-2.26 (m, 1H), 2.23-2.03 (m,3H), 2.02-1.65 (m, 6H), 1.43 (t, J=12.9 Hz, 1H), 1.13 (d, J=6.6 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₅₁ClN₅O₇S: 768.31; found: 767.73.

Example 293

Step 1: Preparation of A-(tert-butylglycyl)-A-methyl glycine (293-1)

To a solution ofN—(N-(tert-butoxycarbonyl)-N-(tert-butyl)glycyl)-N-methylglycine (600mg, 1.98 mmol) in DCM (10 mL) at 0° C. was added TFA (2 mL) slowly. Thereaction mixture was warmed to room temperature and stirred forovernight. It was then concentrated to dryness and used in next stepwith no further purification. LCMS-ESI+: [M+H]⁺ calc'd for C₉H₁₈N₂O₃:203.14; found: 203.10.

Step 2

To the crude intermediate 293-1 (0.4 g, 1.98 mmol) was added 1.0 MNa₂CO₃ aqueous solution (6 mL). The reaction mixture was cooled to 0° C.and 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) (1.03 g, 3.97 mmol) indioxane (12 mL) was gradually added. The reaction mixture was stirred atroom temperature for 14 hours and then was neutralized with 1.0 N HCl(13 mL) aqueous solution to a pH value of 2. It was then extracted withEtOAc (50 mL×2). The organic layers were combined, dried andconcentrated. The crude residue was purified by column chromatographyusing 0-10% MeOH in DCM to afford intermediate 293-2. LCMS-ESI+: [M+H]⁺calc'd for C₂₄H₂₈N₂O₅: 425.21; found: 425.19.

Step 3

Intermediate 293-3 was synthesized in the same manner as Example 18using intermediate 293-2 and Example 359. LCMS-ESI+: [M+H]⁺ calc'd forC₆₂H₇₂ClN₇O₁₀S: 1142.48; found: 1142.08.

Step 4

To a solution of intermediate 293-3 (22 mg, 0.20 mmol) in DMF (1.2 mL)was added piperidine (0.3 mL). The reaction mixture was stirred for 20min and LC/MS showed it went to completion. 0.5 ml of water was added toquench the reaction. The crude mixture was diluted with MeOH (2 mL) andpurified by RP-HPLC (30-100% gradient, 0.1% TFA) to afford Example 293.¹H NMR (400 MHz, Methanol-d4) δ 7.94 (d, J=4.3 Hz, 1H), 7.76 (t, J=8.1Hz, 1H), 7.26-7.03 (m, 4H), 6.94 (t, J=1.1 Hz, 1H), 5.99 (d, J=15.0 Hz,1H), 5.77 (td, J=16.8, 15.4, 8.2 Hz, 1H), 5.44 (ddd, J=37.1, 8.0, 3.8Hz, 1H), 4.28 (d, J=28.4 Hz, 1H), 4.10 (t, J=4.4 Hz, 5H), 4.03-3.84 (m,5H), 3.79 (d, J=1.5 Hz, 3H), 3.69 (t, J=12.5 Hz, 1H), 3.16 (t, J=5.5 Hz,1H), 3.11 (s, 3H), 2.88-2.72 (m, 2H), 2.59-2.42 (m, 2H), 2.20 (s, 3H),2.09 (d, J=13.7 Hz, 1H), 2.01-1.84 (m, 5H), 1.83-1.70 (m, 2H), 1.57 (d,J=7.0 Hz, 3H), 1.49 (d, J=12.7 Hz, 1H), 1.41 (d, J=9.4 Hz, 9H), 1.17 (q,J=3.1 Hz, 3H). LCMS-ESI+[M+H] calculated for C₄₇H₆₂ClN₇O₈S: 920.41;found: 920.20.

Example 294

Example 294 was synthesized in the similar method described herein.LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₃₇H₄₈ClN₅O₅S: 710.3137; found:710.03.

Example 295

Example 291 was synthesized in the same manner as Example 283 using4-(2-iodoethyl)morpholine and Example 279. ¹H NMR (400 MHz, Methanol-d₄)δ 8.09 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.2, 1.9 Hz, 1H),7.25 (s, 1H), 7.19 (dd, J=8.5, 2.3 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 6.93(d, J=8.2 Hz, 1H), 6.21 (dd, J=15.3, 8.7 Hz, 1H), 5.93 (dd, J=15.3, 8.8Hz, 1H), 4.27 (dd, J=14.9, 5.5 Hz, 1H), 4.08 (m, 9H), 3.99-3.76 (m, 8H),3.76-3.57 (m, 4H), 3.59-3.38 (m, 4H), 3.36-3.20 (m, 2H), 3.30 (s, 3H),3.20-3.08 (m, 2H), 2.89-2.73 (m, 2H), 2.54 (m, 2H), 2.33 (m, 1H), 2.12(d, J=13.2 Hz, 1H), 1.96 (m, 2H), 1.83 (m, 3H), 1.47 (t, J=12.4 Hz, 1H),1.25 (d, J=6.9 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₄H₅₇ClFN₆O₈S: 865.4; found: 865.4.

Example 296

Example 296 was synthesized in the same manner as Example 283 usingiodoethane and Example 279. ¹H NMR (400 MHz, Methanol-d₄) δ 8.10 (s,1H), 7.75 (d, J=8.5 Hz, 1H), 7.42-7.31 (m, 1H), 7.19 (s, 1H), 7.18-7.10(m, 2H), 6.91 (d, J=8.2 Hz, 1H), 6.04 (dd, J=15.4, 7.6 Hz, 1H), 5.80(dd, J=15.4, 8.6 Hz, 1H), 4.12-4.02 (m, 5H), 3.98 (d, J=7.5 Hz, 1H),3.82 (m, 5H), 3.72 (d, J=14.4 Hz, 1H), 3.61 (dq, J=9.5, 7.0 Hz, 1H),3.45-3.25 (m, 3H), 3.31 (m, 2H), 3.29 (s, 3H), 3.18-3.06 (m, 1H),2.87-2.71 (m, 3H), 2.51 (s, 2H), 2.24 (d, J=7.7 Hz, 1H), 2.11 (d, J=13.7Hz, 1H), 1.96 (m, 2H), 1.82 (d, J=7.2 Hz, 3H), 1.45 (t, J=11.8 Hz, 1H),1.23-1.12 (m, 6H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₅₀ClN₅O₇S:780.3; found: 780.1.

Example 297 Step 1

To the mixture of tert-butyl 3-oxoazetidine-1-carboxylate (50.0 mg,0.292 mmol) and(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazinedihydrochloride (62.8 mg, 0.292 mmol) in DCE (1.0 mL) at roomtemperature was added Triethylamine (59.1 mg, 0.584 mmol). The resultingmixture was stirred at room temperature for 10 min andsodiumtriacetoxyborohydride (92.9 mg, 0.438 mmol) was added. Theresulting mixture was stirred at room temperature for overnight. Thereaction was then mixed with MeOH, the precipitate was filtered, thefiltrate was purified by combiflash (4 g silica gel, 0-10% 2.0NMeOH/EtOAc). Desired fractions were combined and concentrated to give297-1. 1H NMR (400 MHz, Chloroform-d) δ 3.94-3.75 (m, 5H), 3.73-3.62 (m,2H), 3.24 (t, J=10.7 Hz, 1H), 3.11-3.02 (m, 1H), 2.82-2.71 (m, 2H), 2.68(d, J=11.5 Hz, 1H), 2.54 (dt, J=10.8, 2.3 Hz, 1H), 2.44-2.30 (m, 3H),2.20-2.10 (m, 1H), 1.68 (t, J=10.5 Hz, 1H), 1.41 (s, 9H). LCMS-ESI+(m/z): calcd H+ for C₁₅H₂₇N₃O₃: 298.21; found: 297.98.

Step 2

Intermediate 297-1 (53.2 mg, 0.179 mmol) was dissolved in DCM (1.0 mL)at room temperature. 4 N HCl in 1,4-dioxane (0.224 mL, 0.894 mmol) wasadded slowly. The resulting mixture was stirred at room temperature for2 hrs. The reaction was concentrated, and coevaporated with EtOAc (3×2.0mL) to give 297-2. 1H NMR (400 MHz, Methanol-d4) δ 4.22-4.00 (m, 7H),3.94 (t, J=12.4 Hz, 1H), 3.71-3.50 (m, 5H), 3.46 (d, J=12.6 Hz, 1H),3.18-3.02 (m, 2H), 2.60 (t, J=12.7 Hz, 1H), 2.24 (t, J=11.7 Hz, 1H).LCMS-ESI+ (m/z): calcd H+ for C₁₀H₁₉N₃O:198.15; found: 198.15.

Step 3: Synthesis of Example 297

To a solution of Example 109 (10.0 mg, 0.0167 mmol) in DCM (0.4 mL) wasadded acetonitrile (2.0 mL). To the mixture was added DMAP (10.2 mg,0.084 mmol) and diphenyl carbonate (28.6 mg, 0.134 mmol). The reactionmixture was stirred at room temperature for 3 hrs. To the stirredmixture was added(9aS)-8-(azetidin-3-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinetrihydrochloride (20.5 mg, 0.069 mmol) followed by DIEA (32.4 mg, 0.25mmol). The reaction was then heated at 50° C. for 5 hrs before it wasconcentrated, redissolved in DMF (1.2 mL), filtered and purified byGilson reverse phase prep HPLC. Desired fractions were combined andconcentrated. The residue was diluted with water and frozen dried togive the title compound. 1H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J=8.6Hz, 1H), 7.18 (dd, J=8.4, 2.3 Hz, 1H), 7.14-7.07 (m, 2H), 6.96-6.89 (m,2H), 6.02-5.92 (m, 1H), 5.58 (dd, J=15.3, 9.0 Hz, 1H), 4.31 (dd, J=14.9,6.4 Hz, 1H), 4.21-3.97 (m, 5H), 3.89-3.81 (m, 1H), 3.76 (dd, J=9.1, 3.8Hz, 1H), 3.71-3.63 (m, 1H), 3.54-3.46 (m, 1H), 3.45-3.36 (m, 1H),3.32-3.17 (m, 13H), 3.13-3.04 (m, 2H), 2.87-2.73 (m, 2H), 2.55-2.41 (m,3H), 2.40-2.29 (m, 1H), 2.25-2.04 (m, 4H), 2.00-1.68 (m, 7H), 1.50-1.34(m, 2H), 1.14 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ forC₄₃H₅₇N₆O₆S: 821.37; found: 821.07.

Example 298

Example 298 was synthesized in the same manner as Example 280 usingExample 279. ¹H NMR (400 MHz, Methanol-d₄) δ 8.08 (s, 1H), 8.00 (s, 1H),7.77 (d, J=8.5 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.29 (s, 1H), 7.18 (d,J=8.5 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 4.09 (m,6H), 3.82 (m, 5H), 3.71 (d, J=14.4 Hz, 1H), 3.61 (s, 1H), 3.37 (d, J=4.2Hz, 2H), 3.18-3.04 (m, 1H), 3.02 (s, 3H), 2.88 (s, 3H), 2.80 (m, 2H),2.56 (m, 2H), 2.26 (s, 1H), 2.11 (d, J=13.5 Hz, 1H), 2.01-1.9 (m, 2H),1.76 (m, 4H), 1.67-1.39 (m, 4H), 1.19 (d, J=6.9 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₈H₄₈ClN₅O₇S: 754.3; found: 754.1.

Example 298

Example 299 was synthesized in the same manner as Example 280 usingExample 279. ¹H NMR (400 MHz, Methanol-d₄) δ 8.10 (s, 1H), 7.77 (d,J=8.5 Hz, 1H), 7.41 (dd, J=8.3, 1.8 Hz, 1H), 7.25 (s, 1H), 7.17 (dd,J=8.5, 2.3 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.08(m, 7H), 3.82 (m, 5H), 3.71 (d, J=14.2 Hz, 1H), 3.40 (m, 4H), 3.35 (m,2H), 3.31 (s, 3H), 3.21 (d, J=7.2 Hz, 1H), 3.18-3.07 (m, 1H), 2.90-2.71(m, 2H), 2.62 (m, 1H), 2.48 (m, 1H), 2.36 (m, 1H), 2.11 (d, J=13.5 Hz,1H), 1.96 (m, 3H), 1.77 (d, J=7.4 Hz, 3H), 1.50 (q, J=11.3, 9.2 Hz, 4H),1.16 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₅₀ClN₅O₇S:768.3; found: 768.1.

Example 300

To a stirred solution of 3-methoxy-1-methyl-1H-pyrazole-4-carboxylicacid (6 mg, 0.038 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideHCl (10.75 mg, 0.069 mmol) and 4-(dimethylamino)pyridine (8.45 mg, 0.069mmol) in DCM (5 mL) was added Example 223 (25 mg, 0.035 mmol). Thereaction mixture was stirred at room temperature for 24 hr. Then thereaction mixture was diluted with DCM and water and extracted in DCM.The organic phase was dried over MgSO₄, filtered, concentrated down andpurified on reversed phase chromatography 0.1% TFA 70-95% acetonitrileto give Example 300. 1H NMR (400 MHz, Chloroform-d) δ 11.16 (s, 1H),7.97 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.28-7.17(m, 2H), 7.10 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.11 (dd,J=14.9, 7.7 Hz, 1H), 5.74 (dd, J=15.6, 6.2 Hz, 1H), 5.33 (t, J=5.3 Hz,1H), 4.11 (d, J=5.5 Hz, 3H), 4.07-3.88 (m, 3H), 3.82 (s, 2H), 3.76 (d,J=14.4 Hz, 1H), 3.57 (d, J=61.0 Hz, 2H), 3.42-3.18 (m, 3H), 3.13-2.58(m, 6H), 2.48-2.21 (m, 3H), 2.07-1.47 (m, 13H), 1.40 (t, J=12.8 Hz, 1H),1.28 (s, 2H), 1.19 (d, J=6.2 Hz, 2H), 0.96-0.70 (m, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C₄₄H₅₅ClN₆O₈S: 862.35; found: 862.95.

Example 301

Example 301 was synthesized in the same manner as Example 404 usingdimethylglycine and Example 223. 1H NMR (400 MHz, Chloroform-d) δ 8.10(s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.25-7.12 (m,2H), 7.10 (d, J=2.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.37-6.21 (m, 1H),5.85 (dd, J=15.7, 5.7 Hz, 1H), 5.33 (s, 1H), 4.55 (d, J=18.1 Hz, 1H),4.35 (d, J=14.4 Hz, 1H), 4.15-3.87 (m, 5H), 3.90-3.66 (m, 4H), 3.29 (dd,J=28.4, 13.1 Hz, 3H), 3.04 (s, 5H), 2.78 (d, J=12.3 Hz, 5H), 2.49-2.15(m, 5H), 2.11-1.91 (m, 3H), 1.89-1.62 (m, 4H), 1.38-1.13 (m, 4H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₁H₅₁ClN₆O₇S: 807.32; found: 806.99.

Example 302

Example 302 was synthesize in the same manner as Example 18, usingExample 109 instead of Example 5, and7-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid wasused instead of 3-methoxypropionic acid. 1H NMR (400 MHz, Methanol-d4) δ7.93 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.16 (ddd, J=19.0, 8.6, 2.3 Hz,3H), 6.99-6.88 (m, 2H), 6.07 (dt, J=14.2, 6.5 Hz, 1H), 5.56 (dd, J=15.2,9.3 Hz, 1H), 4.47 (dd, J=14.6, 6.2 Hz, 1H), 4.27 (dd, J=8.2, 4.3 Hz,2H), 4.08 (d, J=1.8 Hz, 3H), 3.91-3.76 (m, 3H), 3.67 (d, J=14.2 Hz, 1H),3.46 (s, 3H), 3.27 (s, 4H), 3.07 (dd, J=15.3, 10.3 Hz, 1H), 2.91-2.69(m, 3H), 2.57-2.28 (m, 5H), 2.17 (dt, J=30.1, 13.2 Hz, 4H), 2.03-1.85(m, 3H), 1.77 (dq, J=17.4, 9.1 Hz, 3H), 1.44 (t, J=12.2 Hz, 1H),1.16-1.05 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₁H₅₀ClN₅O₆S:776.32; found: 776.29.

Example 303

Step 1: Preparation of(1S,2S)-2-(methoxymethyl)cyclopropane-1-carboxylic Acid

A solution of ethyl (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate(640 mg, 4.44 mmol) was suspended in THF (44 mL), cooled to 0° C. andtreated with NaH (213 mg, 8.88 mmol). After 15 minutes, methyl iodide(1.38 mL, 22.2 mmol) was added and the reaction mixture was warmed toRT. After stirring for 1 h, EtOH (22 mL) was added carefully followed by2M NaOH (22 mL, 44 mmol). The reaction mixture was then warmed to 65° C.and stirred at this temperature for 18 h. The mixture was then cooled toRT and poured into a separatory funnel containing 10% HCl. The aqueouslayer was extracted 3× with DCM. The combined organics were dried overMgSO₄, then filtered and concentrated under reduced pressure to provide(1S,2S)-2-(methoxymethyl)cyclopropane-1-carboxylic acid (282 mg), whichwas carried on without further purification. ¹H NMR (400 MHz,Chloroform-d) δ 3.43-3.30 (m, 4H), 3.26 (dd, J=10.4, 6.7 Hz, 1H), 1.76(dddd, J=12.8, 10.4, 7.8, 5.2 Hz, 1H), 1.56 (dt, J=8.6, 4.4 Hz, 1H),1.32-1.21 (m, 1H), 0.93 (ddd, J=8.2, 6.3, 4.3 Hz, 1H).

Step 2: Preparation of Example 303

(1S,2S)-2-(methoxymethyl) cyclopropane-1-carboxylic acid (112 mg, 0.861mmol) was suspended in PhMe (1 mL), then treated with diphenylphosphoryl azide (0.18 mL, 0.84 mmol) and trimethylamine (0.14 mL, 1.0mmol). The stirred reaction mixture was heated to 80° C., then cooled toRT. Example 109 (50 mg, 0.084 mmol) was added and the stirred reactionmixture was heated to 50° C. for 4 h. Upon completion, the reactionmixture was diluted with EtOAc. The organic phase was washed withsaturated NaHCO₃ solution, 5% citric acid and brine, then dried overMgSO₄, filtered, and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography (0% to 40%MeOH/EtOAc), then repurified by HPLC to afford Example 303. ¹H NMR (400MHz, Chloroform-d) δ 7.80-7.34 (m, 1H), 7.23-6.57 (m, 5H), 6.00 (dt,J=14.0, 6.7 Hz, 1H), 5.63 (ddd, J=41.7, 15.4, 8.5 Hz, 1H), 4.40-3.88 (m,3H), 3.88-3.49 (m, 5H), 3.42 (s, 3H), 3.38-3.18 (m, 5H), 3.18-2.89 (m,1H), 2.89-2.52 (m, 3H), 2.52-2.08 (m, 5H), 2.08-1.49 (m, 7H), 1.48-1.19(m, 3H), 1.13 (d, J=6.3 Hz, 3H), 0.98 (dt, J=10.6, 5.4 Hz, 1H),0.92-0.80 (m, 1H), 0.75 (q, J=6.6 Hz, 1H). LCMS-ESI+: calculated forC₃₈H₄₉ClN₄O₆S: 725.3 (M+H); found: 725.8 (M+H).

Example 304 Step 1

Sodium borohydride (494 mg, 13.1 mmol) was added to a solution of5-formyl-1-methyl-pyrrole-3-carboxylic acid (500 mg, 3.27 mmol) inmethanol (10 mL). After 2 hours, more sodium borohydride (494 mg, 13.1mmol) was added. After 5 hours, the reaction was quenched with water (5mL). The methanol was removed under reduced pressure. The aqueous phasewas extracted with ethyl acetate (3×5 mL). The aqueous phases werediluted with ACN and subjected to lyophilization, providing5-(hydroxymethyl)-1-methyl-1H-pyrrole-3-carboxylic acid sodium salt.

Step 2

5-(Hydroxymethyl)-1-methyl-1H-pyrrole-3-carboxylic acid sodium salt fromabove (507 mg, 3.27 mmol) was suspended in tetrahydrofuran (25 mL) andA-methyl-2-pyrrolidone (10 mL). Sodium hydride 60% suspension in mineraloil (250 mg, 6.54 mmol) was added. After 5 minutes, iodomethane (0.61mL, 9.8 mmol) was added. After 16 h, sodium hydride 60% suspension inmineral oil (250 mg, 6.54 mmol) was added. After 5 minutes iodomethane(0.61 mL, 9.8 mmol) were added. After 4 days the reaction was dilutedwith ethyl acetate (100 mL) and washed with water (50 mL), 5% lithiumchloride (2×) and brine (50 mL). The organic phase was dried over sodiumsulfate and the solvent was removed under reduced pressure. The residuewas subjected to flash chromatography (0-100% ethyl acetate/hexanes).The fractions containing product were combined and the solvent wasremoved under reduced pressure, providing methyl5-(methoxymethyl)-1-methyl-1H-pyrrole-3-carboxylate. ¹H NMR (400 MHz,DMSO-d6) δ 7.47 (d, J=1.9 Hz, 1H), 6.43 (d, J=1.8 Hz, 1H), 4.33 (s, 2H),3.68 (s, 3H), 3.61 (s, 3H), 3.20 (s, 3H).

Step 3

A solution of 1 N lithium hydroxide (2.0 mL, 2.0 mmol) was added to asolution of methyl 5-(methoxymethyl)-1-methyl-1H-pyrrole-3-carboxylate(138 mg, 0.75 mmol) in methanol (10 mL). The solution was stirred at 40°C. for 18 hours. The reaction was cooled and the pH was adjusted to 2with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate(3×15 mL). The organic phases were combined and washed with brine, anddried over sodium sulfate. The solvent was removed under reducedpressure providing 5-(hydroxymethyl)-1-methyl-1H-pyrrole-3-carboxylicacid. ¹H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.38 (d, J=1.9 Hz, 1H),6.38 (d, J=1.9 Hz, 1H), 4.32 (s, 2H), 3.60 (s, 3H), 3.20 (s, 3H).

Example 304 was synthesized in the same manner as Example 18 using5-(methoxymethyl)-1-methyl-1H-pyrrole-3-carboxylic acid and Example 109.1H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J=8.5 Hz, 1H), 7.48 (s, 1H),7.29 (d, J=8.2 Hz, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 7.11 (d, J=2.3 Hz,1H), 7.02 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.66-6.59 (m, 1H), 6.22-6.08(m, 1H), 5.60-5.46 (m, 2H), 4.47-4.33 (m, 3H), 4.12-4.00 (m, 2H), 3.96(d, J=11.9 Hz, 0H), 3.88 (d, J=15.1 Hz, 1H), 3.81 (dd, J=9.1, 3.2 Hz,1H), 3.73-3.62 (m, 4H), 3.27 (m, 4H), 3.04 (dd, J=15.2, 9.6 Hz, 1H),2.88-2.70 (m, 2H), 2.57 (m, 1H), 2.42 (m, 3H), 2.12 (m, 4H), 1.94 (m,3H), 1.77 (m, 3H), 1.49-1.28 (m, 1H), 1.08 (d, J=5.9 Hz, 3H). LCMS-ESI+:calc'd for C₄₀H₄₉ClN₄O₆S: 749.31 (M+H); found: 749.85 (M+H).

Example 305

Step 1

Synthesis of 305-1: To the mixture of3-amino-1-methyl-cyclobutanecarboxylic acid (250 mg, 1.94 mmol) in MeOH(1.0 mL) at room temperature was added 4 N HCl in 1,4-dioxane (1.94 mL,7.74 mmol). The resulting mixture was stirred at room temperature for 2days. The reaction was concentrated, co-evaporated with EtOAc (3×), andfurther dried over the vacuum line to give 305-1. 1H NMR (400 MHz,Methanol-d4) δ 3.95-3.80 (m, 1H), 3.74 (s, 3H), 2.65-2.52 (m, 2H),2.40-2.25 (m, 2H), 1.46 (s, 3H).

Step 2

Example 305 was synthesized in the same manner as Example 75 usingExample 109 and 305-1 and DIEA. 1H NMR (400 MHz, Methanol-d4) δ 7.74 (d,J=8.4 Hz, 1H), 7.23-7.09 (m, 3H), 6.99 (s, 1H), 6.91 (d, J=8.1 Hz, 1H),6.10-5.98 (m, 1H), 5.65-5.54 (m, 1H), 4.37-4.22 (m, 2H), 4.11-4.01 (m,2H), 3.89-3.74 (m, 3H), 3.73-3.65 (m, 4H), 3.27 (s, 3H), 3.12-3.02 (m,1H), 2.89-2.71 (m, 2H), 2.53-2.35 (m, 5H), 2.32-2.23 (m, 2H), 2.23-2.16(m, 1H), 2.16-2.08 (m, 2H), 2.00-1.71 (m, 7H), 1.48-1.40 (m, 4H), 1.13(d, J=6.7 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ for C₄₀H₅₁ClN₄O₇S: 767.32;found: 766.77.

Example 306

Example 306 was synthesized in a manner similar to Example 214 using(S)-2-(methoxymethyl)oxirane instead of (R)-2-(methoxymethyl)oxirane. 1HNMR (400 MHz, Acetone-d6) δ 7.78 (d, J=8.5 Hz, 1H), 7.50-7.38 (m, 1H),7.34 (d, J=8.2 Hz, 1H), 7.27-7.21 (m, 2H), 7.14 (d, J=2.3 Hz, 1H), 6.91(d, J=8.2 Hz, 1H), 6.31 (s, 1H), 6.23-6.10 (m, 1H), 5.62 (dd, J=15.5,8.0 Hz, 1H), 4.93 (d, J=14.4 Hz, 1H), 4.74 (d, J=14.5 Hz, 1H), 4.26-3.94(m, 5H), 3.94-3.81 (m, 2H), 3.81-3.71 (m, 2H), 3.64 (dd, J=10.4, 5.4 Hz,1H), 3.55 (dd, J=10.4, 4.8 Hz, 1H), 3.43 (d, J=14.4 Hz, 1H), 3.39 (s,3H), 3.24 (s, 3H), 3.14 (dd, J=15.1, 10.4 Hz, 1H), 2.96-1.39 (m, 16H),1.13 (d, J=6.6 Hz, 3H). LCMS: 791.0.

Example 307

Example 307 was synthesized in the same manner as Example 75 using(1R,2R)-2-(methoxymethyl)cyclobutan-1-amine and Example 109. 1H NMR (400MHz, Methanol-d4) δ 7.76 (d, J=8.4 Hz, 1H), 7.20 (dd, J=20.9, 8.3 Hz,2H), 7.13 (s, 1H), 7.03 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.08 (d, J=15.2Hz, 1H), 5.59 (dd, J=15.4, 9.0 Hz, 1H), 4.25 (s, 1H), 4.04 (dd, J=19.9,7.0 Hz, 3H), 3.91-3.63 (m, 4H), 3.46 (dd, J=11.2, 5.8 Hz, 2H), 3.36 (s,3H), 3.27 (s, 3H), 3.09 (dd, J=15.1, 10.2 Hz, 1H), 2.89-2.73 (m, 2H),2.44 (d, J=35.2 Hz, 4H), 2.20 (dd, J=23.2, 5.7 Hz, 2H), 1.96 (s, 3H),1.89-1.70 (m, 4H), 1.56-1.40 (m, 3H), 1.13 (d, J=6.7 Hz, 3H), 0.91 (d,J=7.1 Hz, 1H), 0.61 (s, 1H), 0.12 (d, J=12.1 Hz, 1H). LCMS-ESI+[M+H]⁺calc'd for C₃₉H₅₁ClN₄O₆S: 739.32; found:738.84.

Example 308

Example 308 was synthesized in the same manner as Example 18 usingExample 109 and 1-methyl-5-(morpholinomethyl)-1H-pyrrole-3-carboxylicacid (prepared from 5-formyl-1-methyl-pyrrole-3-carboxylic acid andmorpholine using similar procedure to Example 309-step 1). ¹H NMR (400MHz, Methanol-d4) δ 7.71 (d, J=1.9 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.37(dd, J=8.2 Hz, 1H), 7.28 (s, 1H), 7.01 (dd, J=12.9, 2.1 Hz, 2H), 6.77(d, J=8.3 Hz, 1H), 6.70 (s, 1H), 6.20 (dd, J=15.1, 7.7 Hz, 1H), 5.73(dd, J=15.4, 8.2 Hz, 1H), 4.44 (s, 2H), 4.15 (dd, J=14.7, 7.1 Hz, 1H),4.02-3.85 (m, 3H), 3.80 (s, 4H), 3.78-3.71 (m, 1H), 3.61 (d, J=14.4 Hz,1H), 3.50 (d, J=14.5 Hz, 1H), 3.14 (dd, J=15.2, 10.7 Hz, 1H), 3.02-2.82(m, 2H), 2.82-2.65 (m, 1H), 2.65-2.44 (m, 1H), 2.34 (d, J=15.2 Hz, 3H),2.12-1.96 (m, 1H), 1.96-1.79 (m, 3H), 1.32 (d, J=10.5 Hz, 2H), 1.19 (d,J=6.2 Hz, 3H). LCMS-ESI+: calc'd for C₄₃H₅₄ClN₅O₆S: 804.35 (M+H); found:804.56 (M+H).

Example 309

Step 1

1-(Oxetan-3-yl)piperazine was added to a solution of the5-formyl-1-methyl-pyrrole-3-carboxylic acid (50 mg, 0.327 mmol) intetrahydrofuran (3 mL). The solution was stirred at room temperature for2 hours. Sodium borohydride (346 mg, 9 mmol) and methanol (0.5 mL) wereadded. After 2 h, the reaction was quenched with water (2 mL) andtrifluoroacetic acid (0.3 mL). The solution was subjected to preparativeHPLC. The fractions containing product were combined and subjected tolyophilization, providing1-methyl-5-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-1H-pyrrole-3-carboxylicacid. ¹H NMR (400 MHz, Methanol-d4) δ 7.49 (d, J=1.8 Hz, 1H), 6.75 (d,J=1.8 Hz, 1H), 4.76 (t, J=6.9 Hz, 2H), 4.64 (dd, J=7.0, 5.6 Hz, 2H),4.23 (s, 2H), 3.83 (t, J=6.1 Hz, 1H), 3.77 (s, 3H), 3.29-3.10 (m, 4H),2.81 (s, 5H).

Step 2

Example 308 was synthesized in the same manner as Example 18 usingExample 109 and1-methyl-5-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-1H-pyrrole-3-carboxylicacid. 1H NMR (400 MHz, Methanol-d4) δ 7.68 (d, J=1.8 Hz, 1H), 7.63 (d,J=8.6 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.05 (dd, J=14.4, 2.1 Hz, 2H),6.98 (s, 3H), 6.93 (s, 2H), 6.84 (d, J=8.2 Hz, 1H), 6.14 (dd, J=15.0,7.6 Hz, 1H), 5.68 (dd, J=15.4, 8.3 Hz, 1H), 4.78 (t, J=6.9 Hz, 2H), 4.66(t, J=6.3 Hz, 2H), 4.20 (d, J=14.2 Hz, 3H), 4.01 (s, 2H), 4.00-3.90 (m,0H), 3.65 (d, J=14.5 Hz, 1H), 3.43 (d, J=14.4 Hz, 1H), 3.20-3.02 (m,1H), 2.86 (d, J=16.7 Hz, 1H), 2.76 (dq, J=16.7, 8.7, 7.4 Hz, 2H), 2.49(s, 2H), 2.30 (d, J=15.5 Hz, 2H), 2.22-2.05 (m, 1H), 1.97 (d, J=9.0 Hz,1H), 1.84 (s, 0H), 1.40 (t, J=12.3 Hz, 1H), 1.17 (d, J=6.1 Hz, 3H).LCMS-ESI+: calc'd for C₄₆H₅₉ClN₆O₆S: 859.39 (M+H); found: 859.46 (M+H).

Example 310

Example 310 was prepared in a similar manner to Example 75 using(1R,2R)-2-(difluoromethyl)cyclopropan-1-amine, triethylamine and Example109. 1H NMR (400 MHz, Methanol-d4) δ 7.72 (d, J=8.4 Hz, 1H), 7.18 (d,J=8.3 Hz, 1H), 7.15-7.05 (m, 2H), 6.96 (s, 1H), 6.91 (d, J=8.1 Hz, 1H),6.10-6.00 (m, 1H), 5.83 (td, J=57.3, 4.2 Hz, 1H), 5.61 (dd, J=15.3, 9.0Hz, 1H), 4.27 (d, J=14.4 Hz, 1H), 4.06 (d, J=1.8 Hz, 2H), 3.84 (d,J=15.1 Hz, 1H), 3.77 (dd, J=9.0, 3.6 Hz, 1H), 3.67 (d, J=14.2 Hz, 1H),3.30-3.23 (m, 4H), 3.08 (dd, J=15.2, 10.2 Hz, 1H), 2.78 (ddd, J=22.7,18.6, 10.0 Hz, 3H), 2.45 (dt, J=34.4, 13.8 Hz, 3H), 2.21 (dd, J=14.9,6.4 Hz, 1H), 2.15-2.04 (m, 1H), 2.04-1.87 (m, 2H), 1.82 (dt, J=21.0, 8.2Hz, 2H), 1.59-1.48 (m, 1H), 1.43 (t, J=11.9 Hz, 1H), 1.31 (s, 2H), 1.14(d, J=6.5 Hz, 3H), 1.09 (q, J=6.3 Hz, 1H), 1.04-0.85 (m, 1H). LCMS-ESI+:calc'd for LCMS-ESI+: calc'd for C₃₇H₄₅ClF₂N₄O₅S: 731.28 (M+H); found:731.13 (M+H).

Example 311

Example 311 was prepared in a similar manner as Example 75 using(1S,2S)-2-(difluoromethyl)cyclopropan-1-amine, triethylamine and Example109. 1H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J=8.5 Hz, 1H), 7.18 (dt,J=9.2, 3.1 Hz, 2H), 7.10 (d, J=2.3 Hz, 1H), 6.93 (d, J=1.9 Hz, 1H), 6.82(d, J=8.0 Hz, 1H), 6.17 (dd, J=14.9, 7.4 Hz, 1H), 5.84 (td, J=57.6, 4.0Hz, 1H), 5.48 (dd, J=15.2, 9.3 Hz, 1H), 4.38 (dd, J=14.1, 6.9 Hz, 1H),4.08-3.97 (m, 2H), 3.88 (d, J=15.0 Hz, 1H), 3.85-3.74 (m, 2H), 3.65 (d,J=14.1 Hz, 1H), 3.26 (m, 4H), 3.01 (dd, J=15.2, 10.0 Hz, 1H), 2.91-2.69(m, 3H), 2.58 (dd, J=12.3, 6.2 Hz, 1H), 2.41 (dq, J=27.3, 9.2, 8.2 Hz,2H), 2.18-2.01 (m, 3H), 1.99-1.85 (m, 2H), 1.76 (ddt, J=28.8, 18.5, 9.4Hz, 2H), 1.55-1.30 (m, 3H), 1.06 (m, 4H), 0.92-0.79 (m, 1H). LCMS-ESI+:calc'd for C₃₇H₄₅ClF₂N₄O₅S: 731.28 (M+H); found: 731.02 (M+H).

Example 312

Example 312 was prepared in a similar manner to Example 75 using(1R,2S)-2-methoxy-2-methylcyclopropan-1-amine, triethylamine and Example109. The stereochemistry is arbitrarily assigned but not absolute. 1HNMR (400 MHz, Methanol-d4) δ 7.76 (d, J=8.5 Hz, 1H), 7.23 (d, J=8.3 Hz,1H), 7.18 (dd, J=8.5, 2.3 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.02 (s, 1H),6.90 (d, J=8.2 Hz, 1H), 6.06 (dt, J=14.3, 6.8 Hz, 1H), 5.58 (dd, J=15.3,8.9 Hz, 1H), 4.28 (dd, J=14.9, 6.5 Hz, 1H), 4.13-4.00 (m, 2H), 3.86 (d,J=14.9 Hz, 1H), 3.78 (dd, J=8.9, 3.7 Hz, 1H), 3.68 (d, J=14.2 Hz, 1H),3.38 (s, 3H), 3.30-3.25 (m, 4H), 3.07 (dd, J=15.2, 10.2 Hz, 1H),2.90-2.74 (m, 2H), 2.70 (dd, J=8.0, 4.8 Hz, 1H), 2.54-2.43 (m, 1H), 2.38(t, J=9.1 Hz, 1H), 2.20 (dt, J=14.6, 7.3 Hz, 1H), 2.12 (d, J=13.4 Hz,2H), 2.01-1.87 (m, 2H), 1.87-1.69 (m, 3H), 1.45 (d, J=12.1 Hz, 1H), 1.39(s, 3H), 1.31 (s, 1H), 1.13 (d, J=6.7 Hz, 3H), 0.93-0.84 (m, 1H), 0.72(t, J=5.7 Hz, 1H). LCMS-ESI+: calc'd for C₃₈H₄₉ClN₄O₆S: 725.31 (M+H);found: 726.03 (M+H).

Example 313

Example 313 was prepared in a similar manner to Example 312 using(1S,2R)-2-methoxy-2-methylcyclopropan-1-amine, triethylamine and Example109. The stereochemistry is arbitrarily assigned but not absolute.LCMS-ESI+: calc'd for C₃₈H₄₉ClN₄O₆S: 725.31 (M+H); found: 726.20 (M+H).

Example 314

Step 1: Synthesis of 314-1

To the mixture of methyl 3-amino-1-methyl-cyclobutanecarboxylate HClsalt (248 mg, 1.38 mmol) in DCM (6.0 mL) at room temperature was addedDIEA (537 mg, 4.15 mmol) followed by di-tert-butyl dicarbonate (362 mg,1.66 mmol). The resulting mixture was stirred at rom temperature forovernight. The reaction was concentrated, redissolved in EtOAc, washedwith 1N HCl, sat. NaHCO₃, brine, dried over sodium sulfate, filtered,and concentrated, further dried over the vacuum line to give 314-1. 1HNMR (400 MHz, Chloroform-d) δ 4.88-4.68 (m, 1H), 4.38-4.20 (m, 1H), 3.71(s, 3H), 2.36-2.24 (m, 4H), 1.45 (s, 9H), 1.42 (s, 3H).

Step 2

Synthesis of 314-2: 314-1 (337 mg, 1.39 mmol) was dissolved in THF (7.0mL), cooled to 0° C. 1.0 N superhydride in THF (2.77 mL, 2.77 mmol) wasadded. The reaction was allowed to warm up to room temperature as icemelted overnight. The reaction was slowly quenched with sat. NH₄Cl, anddiluted with EtOAc. The organic layer was washed with brine, dried oversodium sulfate, filtered, and concentrated to give a crude product. Thecrude product was purified by combiflash (12 g silica gel, 0-100%EtOAc/Hexanes), detected by ELS detector. Desired fractions werecombined and concentrated to give 314-2 (110.0 mg). 1H NMR (400 MHz,Chloroform-d) δ 4.18-4.08 (m, 1H), 3.54 (d, 1H), 3.36 (d, J=2.0 Hz, 1H),2.09-1.99 (m, 2H), 1.92-1.78 (m, 2H), 1.43 (s, 9H), 1.15-1.09 (m, 3H).

Step 3: Synthesis of 314-3

314-2 (110 mg, 0.51 mmol) was treated with DCM (2.0 mL) and 4 N HCl in1,4-dioxane (0.5 mL) at rt for 1 hr. The reaction was concentrated,coevaporated with EtOAc (3×3.0 mL) and further dried over the vacuumline to give 314-3.

Step 4

Example 314 was synthesized in the same manner as Example 75 usingExample 109 and 314-3 and DIEA. 1H NMR (400 MHz, Methanol-d4) δ 7.70 (d,J=8.6 Hz, 1H), 7.26-7.18 (m, 1H), 7.12-7.03 (m, 2H), 7.00 (s, 1H), 6.88(d, J=8.2 Hz, 1H), 6.12-6.00 (m, 1H), 5.68-5.56 (m, 1H), 4.32-4.18 (m,2H), 4.08-3.98 (m, 2H), 3.87-3.74 (m, 3H), 3.66 (d, J=14.2 Hz, 1H), 3.35(s, 2H), 3.29 (s, 3H), 3.08 (dd, J=15.2, 9.9 Hz, 1H), 2.89-2.70 (m, 2H),2.59-2.39 (m, 3H), 2.25-2.01 (m, 6H), 1.98-1.74 (m, 8H), 1.46-1.35 (m,1H), 1.18 (s, 3H), 1.14 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ forC₃₉H₅₁ClN₄O₆S: 739.32; found: 738.88.

Example 315

Example 315 was synthesized in the same manner as Example 316, usingintermediate 316-3 and Example 109. The absolute configuration of thecis cyclopropane stereocenters has not been determined and is denotedarbitrarily. LCMS-ESI+ (m/z): [M+H]⁺ calc'd for C₃₈H₄₉ClN₄O₆S: 725.3134;found: 724.89. ¹H NMR (400 MHz, Methanol-t/4) δ 7.73 (d, J=8.5 Hz, 1H),7.20 (d, J=8.2 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H),6.99 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.03 (dd, J=14.9, 7.5 Hz, 1H),5.57 (dd, J=15.2, 8.9 Hz, 1H), 4.26 (dd, J=14.8, 6.6 Hz, 1H), 4.10-3.98(m, 2H), 3.83 (d, J=15.0 Hz, 2H), 3.76 (dd, J=8.9, 3.7 Hz, 1H), 3.66 (d,J=14.2 Hz, 1H), 3.54-3.36 (m, 2H), 3.34 (s, 3H), 3.33-3.25 (m, 1H), 3.26(s, 3H), 3.05 (dd, J=15.2, 10.2 Hz, 1H), 2.87-2.68 (m, 3H), 2.54-2.29(m, 3H), 2.25-2.04 (m, 3H), 2.02-1.67 (m, 6H), 1.42 (t, J=12.6 Hz, 1H),1.35-1.22 (m, 1H), 1.12 (d, J=6.4 Hz, 3H), 1.02 (ddd, J=9.0, 7.4, 5.7Hz, 1H), 0.53 (td, J=6.0, 4.4 Hz, 1H).

Example 316

Step 1

A solution of rac-[(1R*,2S*)-2-aminocyclopropyl]methanol (1 equiv, 3.44mmol, 300 mg) in triethylamine (4 equiv, 13.8 mmol, 1.92 mL) and THF (15mL) was treated with (4-nitrophenyl) [(1S)-1-phenylethyl] carbonate (1equiv, 3.44 mmol, 989 mg). The reaction mixture was stirred overnight atroom temperature, then concentrated and purified by silica gelchromatography (EtOAc/hexanes) to afford the desired product as amixture of diastereomers 316-2/316-3 (375 mg). The diastereomericmixture was purified by chiral SFC (IC column, 15% EtOH) to afford 316-2(RT=1.52 min; 186 mg) and 316-3 (RT=1.14 min; 191 mg). The absolutestereochemistry of 316-2 and 316-3 has not been determined and isdenoted arbitrarily.

Intermediate 316-2:

¹H NMR (400 MHz, Chloroform-d) δ 7.41-7.27 (m, 5H), 5.81 (q, J=6.6 Hz,1H), 5.03 (s, 1H), 3.96 (d, J=11.8 Hz, 1H), 3.32 (s, 1H), 3.18 (t,J=11.2 Hz, 1H), 2.62 (q, J=6.9, 6.5 Hz, 1H), 1.53 (d, J=6.6 Hz, 3H),1.39 (q, J=7.6 Hz, 1H), 0.93 (ddd, J=9.3, 7.2, 5.7 Hz, 1H), 0.28 (td,J=6.3, 4.2 Hz, 1H).

Intermediate 316-3:

¹H NMR (400 MHz, Chloroform-d) δ 7.43-7.29 (m, 5H), 5.82 (q, J=6.6 Hz,1H), 5.02 (s, 1H), 3.87 (d, J=12.2 Hz, 1H), 3.20-2.94 (bs, 1H), 3.03 (t,J=11.2 Hz, 1H), 2.67 (d, J=5.4 Hz, 1H), 1.56 (d, J=6.6 Hz, 3H), 1.37(ddp, J=13.6, 6.7, 4.0, 3.4 Hz, 1H), 0.93 (dt, J=9.4, 6.7 Hz, 1H), 0.25(d, J=5.5 Hz, 1H).

Step 2

To a solution of intermediate 316-2 (1 equiv, 0.149 mmol, 35 mg) inCH₂Cl₂ (0.75 mL) was added sequentially powdered molecular sieves, 4 Å(1 wt equiv, 35 mg), 1,8-bis(dimethylamino)naphthalene (2.5 equiv, 0.372mmol, 79.7 mg) and 1,8-bis(dimethylamino)naphthalene (2 equiv, 0.298mmol, 44.0 mg). The reaction mixture was stirred at room temperature for5 hours, filtered across Celite, and eluted with EtOAc. The filtrate waswashed with 1 N HCl, water, and brine then dried with sodium sulfate,filtered and concentrated. The crude reaction mixture was purified bysilica gel chromatography (EtOAc/hexanes) to afford the desiredintermediate 316-4. ¹H NMR (400 MHz, Chloroform-d) δ 7.42-7.26 (m, 5H),5.82 (q, J=6.7 Hz, 1H), 5.26-4.88 (m, 1H), 3.60 (dd, J=10.4, 6.1 Hz,1H), 3.38-3.22 (m, 1H), 3.35 (s, 3H), 2.72 (tdd, J=6.9, 4.1, 2.0 Hz,1H), 1.54 (d, J=6.6 Hz, 3H), 1.28 (ddt, J=15.1, 8.6, 6.3 Hz, 1H), 1.00(q, J=12 Hz, 1H), 0.50 (q, J=5.4 Hz, 1H).

Step 3

Intermediate 316-4 was treated with 4 N HCl/dioxane (1.5 mL), sealed andstirred at room temperature overnight. The reaction mixture wasconcentrated under a stream of argon, then further dried under highvacuum for 30 minutes to afford crude intermediate 316-5, which wascarried on directly to Step 4.

Step 4

A 4-dram vial was charged with Example 109 (1 equiv, 0.017 mmol, 10 mg),diphenyl carbonate (6 equiv, 0.10 mmol, 21.5 mg),N,N-dimethylaminopyridine (4 equiv, 0.067 mmol, 8.2 mg) and MeCN (0.75mL). The reaction vial was sealed and stirred at room temperatureovernight. The reaction mixture was then treated with triethylamine (25equiv, 0.42 mmol, 0.06 mL), combined with crude intermediate 316-5 fromStep 3 and heated to 50° C. for 3 hours. The reaction mixture was cooledto room temperature, concentrated and purified by preparative HPLC(60-100% MeCN in water, 0.1% TFA) to afford Example 316. The absoluteconfiguration of the cis cyclopropane stereocenters has not beendetermined and is denoted arbitrarily. LCMS-ESI+ (m/z): [M+H]⁺ calc'dfor C₃₈H₄₉ClN₄O₆S: 725.3134; found: 724.74. ¹H NMR (400 MHz,Methanol-d₄) δ 7.73 (d, J=8.5 Hz, 1H), 7.25-7.12 (m, 2H), 7.10 (d, J=2.2Hz, 1H), 6.99 (s, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.09-5.96 (m, 1H), 5.57(dd, J=15.3, 8.9 Hz, 1H), 4.26 (dd, J=14.8, 6.4 Hz, 1H), 4.11-3.99 (m,2H), 3.89-3.78 (m, 2H), 3.76 (dd, J=8.9, 3.6 Hz, 1H), 3.66 (d, J=14.2Hz, 1H), 3.60-3.45 (m, 1H), 3.46-3.37 (m, 1H), 3.35 (s, 3H), 3.30-3.25(m, 1H), 3.25 (s, 3H), 3.05 (dd, J=15.2, 10.2 Hz, 1H), 2.88-2.67 (m,3H), 2.54-2.29 (m, 3H), 2.26-2.04 (m, 3H), 2.01-1.66 (m, 6H), 1.42 (t,J=12.3 Hz, 1H), 1.29 (p, J=7.5 Hz, 1H), 1.12 (d, J=6.7 Hz, 3H), 1.02(ddd, J=9.1, 7.5, 5.7 Hz, 1H), 0.50 (q, J=5.6 Hz, 1H).

Example 317

Example 317 was synthesized in the same manner as Example 75, usingExample 109 and (1S,2R)-2-methoxycyclopropanamine hydrochloride.Triethylamine (40 equiv) was also added to the reaction mixture (Step2). LCMS-ESI+ (m/z): [M+H]⁺ calc'd for C₃₇H₄₇ClN₄O₆S: 711.2978; found:710.98. ¹H NMR (400 MHz, Methanol-t/4) δ 7.74 (d, J=8.5 Hz, 1H), 7.20(d, J=8.2 Hz, 1H), 7.16 (dd, J=8.5, 2.3 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H),7.00 (s, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.03 (dd, J=14.9, 7.4 Hz, 1H),5.57 (dd, J=15.3, 8.9 Hz, 1H), 4.26 (dd, J=14.8, 6.5 Hz, 1H), 4.12-3.97(m, 2H), 3.84 (d, J=14.9 Hz, 2H), 3.76 (dd, J=8.9, 3.7 Hz, 1H), 3.66 (d,J=14.2 Hz, 1H), 3.42 (s, 3H), 3.30-3.26 (m, 2H), 3.25 (s, 3H), 3.05 (dd,J=15.2, 10.2 Hz, 1H), 2.87-2.69 (m, 3H), 2.55-2.29 (m, 3H), 2.25-2.04(m, 3H), 2.02-1.64 (m, 6H), 1.42 (t, J=12.2 Hz, 1H), 1.12 (d, J=6.6 Hz,3H), 0.96 (dt, J=8.2, 6.8 Hz, 1H), 0.55 (q, J=4.6 Hz, 1H).

Example 318

Example 318 was synthesized in the same manner as Example 75, usingExample 109 and (1R,2S)-2-methoxycyclopropanamine hydrochloride.Triethylamine (40 equiv) was also added to the reaction mixture (Step2). LCMS-ESI+ (m/z): [M+H]⁺ calc'd for C₃₇H₄₇ClN₄O₆S: 711.2978; found:710.64. ¹H NMR (400 MHz, Methanol-d₄) δ 7.73 (d, J=8.5 Hz, 1H), 7.20 (d,J=8.1 Hz, 1H), 7.15 (dd, J=8.5, 2.3 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H),6.99 (s, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.03 (dd, J=14.9, 7.6 Hz, 1H),5.57 (dd, J=15.3, 8.9 Hz, 1H), 4.26 (dd, J=14.8, 6.5 Hz, 1H), 4.11-3.97(m, 2H), 3.83 (d, J=14.9 Hz, 2H), 3.76 (dd, J=8.9, 3.7 Hz, 1H), 3.66 (d,J=14.2 Hz, 1H), 3.41 (s, 3H), 3.29-3.26 (m, 2H), 3.25 (s, 3H), 3.05 (dd,J=15.2, 10.2 Hz, 1H), 2.87-2.66 (m, 3H), 2.56-2.29 (m, 3H), 2.25-2.04(m, 3H), 2.01-1.66 (m, 6H), 1.41 (t, J=12.4 Hz, 1H), 1.11 (d, J=6.4 Hz,3H), 0.97 (q, J=7.0 Hz, 1H), 0.59 (dd, J=7.5, 4.0 Hz, 1H).

Example 319

Step 1

A round bottom flask was charged with starting ethyl3-hydroxy-1-methyl-4-pyrazolecarboxylate (100 mg, 0.588 mmol). The flaskwas placed under high vacuum for 5 min, then backfilled with nitrogenatmosphere. DMF (3 mL) was added, followed by sodium hydride (60%dispersion in mineral oil, 27 mg, 1.2 equiv.) at 20° C. The flask wasstirred at 20° C. for 60 min, then 4-(2-iodoethyl)morpholine (184 mg,1.3 equiv.) was added. The reaction was stirred at 80° C. for 16 hr. Thereaction was removed from heating and allowed to cool to 20° C., thenthe reaction was quenched with water and extracted five times into ethylacetate. The combined organic phases were washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo to provide 120 mgcrude product. Silica gel TLC (95:5 dichloromethane:methanol) of thecrude product indicated complete consumption of starting aminopyrazole(Rf ˜0.60) and one new UV-active product (Rf 0.50). The resultingresidue was dissolved in dichloromethane and purified by flash columnchromatography (silica gel, 12 g, 0 to 10% methanol in dichloromethane).The major UV-active product eluted at 5% dichloromethane. Fractions wereassayed by silica gel TLC. The fractions containing the major UV-activeproduct were collected and concentrated in vacuo to give ethyl1-methyl-3-(2-morpholinoethoxy)-1H-pyrazole-4-carboxylate (120 mg). ¹HNMR (400 MHz, Chloroform-d) δ 7.63 (s, 1H), 4.37 (t, J=5.7 Hz, 2H), 4.21(q, J=7.1 Hz, 2H), 3.71 (s, 3H), 3.72-3.69 (m, 4H), 2.82 (t, J=5.7 Hz,2H), 2.61 (t, J=4.7 Hz, 4H), 1.28 (t, J=7.1 Hz, 3H). LCMS-ESI+ (m/z):[M+H]⁺ calculated for C₁₃H₂₁N₃O₄: 284.2; found: 284.1.

Step 2

To a glass screwtop vial charged with ethyl1-methyl-3-(2-morpholinoethoxy)-1H-pyrazole-4-carboxylate (120 mg, 0.424mmol) was added THF (4.2 mL), then sodium hydroxide (2 M in water, 0.96mL). The resulting mixture was stirred vigorously in a metal heatingblock warmed to 60° C. for 12 hr, at which point silica gel TLC (95:5dichloromethane:methanol) indicated nearly complete consumption ofstarting ethyl ester. The reaction was quenched with 1 N HCl (approx. 2mL), added dropwise until pH 4-5 by pH paper. The resulting mixture wasextracted three times with ethyl acetate. Then the aqueous phase wasconcentrated in vacuo to give1-methyl-3-(2-morpholinoethoxy)-1H-pyrazole-4-carboxylic acid, in atleast 95% purity by NMR, contaminated with an unidentified amount ofsodium chloride (60 mg). ¹H NMR (400 MHz, Methanol-d₄) δ 7.80 (s, 1H),4.49 (t, J=4.9 Hz, 2H), 3.88 (t, J=4.6 Hz, 4H), 3.74 (s, 3H), 3.27 (t,J=5.0 Hz, 2H), 3.11 (t, J=4.5 Hz, 4H). LCMS-ESI+ (m/z): [M+H]⁺calculated for C₁₁H₁₇N₃O₄: 256.1; found: 256.1.

Step 3

Example 319 was prepared in a similar manner as Example 18 using1-methyl-3-(2-morpholinoethoxy)-1H-pyrazole-4-carboxylic acid andExample 109. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 7.98 (s, 1H), 7.71 (d,J=8.5 Hz, 1H), 7.30 (dd, J=8.2, 1.9 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H),7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 6.90 (d, J=8.3 Hz,1H), 6.04 (dt, J=14.5, 6.9 Hz, 1H), 5.58 (dd, J=15.6, 7.6 Hz, 1H), 4.66(dtt, J=13.0, 9.4, 4.6 Hz, 2H), 4.06 (d, J=12.2 Hz, 1H), 4.04-3.97 (m,2H), 3.88 (dd, J=14.8, 7.3 Hz, 1H), 3.83-3.77 (m, 1H), 3.75 (s, 3H),3.71 (d, J=14.3 Hz, 5H), 3.60 (s, 2H), 3.38 (d, J=14.4 Hz, 1H), 3.21 (s,3H), 3.07 (dd, J=15.2, 10.8 Hz, 3H), 2.86-2.63 (m, 3H), 2.52 (dt,J=18.7, 7.6 Hz, 2H), 2.41 (td, J=9.0, 4.2 Hz, 1H), 2.34-2.21 (m, 1H),2.16 (dt, J=15.0, 7.6 Hz, 1H), 2.09-2.00 (m, 1H), 1.90 (dd, J=9.1, 5.1Hz, 3H), 1.84-1.60 (m, 5H), 1.41 (dt, J=14.8, 7.7 Hz, 1H), 1.06 (d,J=6.9 Hz, 3H). LCMS-ESI+ (m/z): [M+H]⁺ calculated for C₄₃H₅₅ClN₆O₇S:835.4; found: 835.3.

Example 320

Example 320 was synthesized in the same manner as Example 75 usingExample 109 and 4-methoxypiperidine. 1H NMR (400 MHz, Methanol-d4) δ7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.3 Hz, 1H), 7.14-7.07 (m, 2H),6.94 (d, J=8.2 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 5.96 (dt, J=14.2, 6.7Hz, 1H), 5.58 (dd, J=15.2, 9.3 Hz, 1H), 4.38 (dd, J=14.9, 6.3 Hz, 1H),4.13-4.04 (m, 2H), 4.04-3.89 (m, 2H), 3.85 (d, J=15.2 Hz, 1H), 3.76 (dd,J=9.3, 3.7 Hz, 1H), 3.67 (d, J=14.1 Hz, 1H), 3.63-3.54 (m, 1H),3.52-3.43 (m, 1H), 3.39 (s, 3H), 3.31-3.30 (m, 1H), 3.28-3.24 (m, 4H),3.08 (dd, J=15.3, 10.3 Hz, 1H), 2.87-2.71 (m, 2H), 2.54-2.42 (m, 2H),2.38-2.27 (m, 1H), 2.22-2.06 (m, 3H), 1.99-1.69 (m, 9H), 1.58-1.39 (m,3H), 1.14 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ forC₃₉H₅₁ClN₄O₆S: 739.32; found: 738.84.

Example 321

Example 321 was synthesized in the same manner as Example 75 usingtrans-2-(difluoromethyl)cyclopropan-1-amine hydrochloride andintermediate 266-2. 1H NMR (400 MHz, Methanol-d4) δ 7.72 (d, J=8.5 Hz,1H), 7.15 (t, J=9.9 Hz, 2H), 7.09 (s, 1H), 6.99 (s, 1H), 6.89 (d, J=8.2Hz, 1H), 5.94 (d, J=13.4 Hz, 1H), 5.81 (d, J=4.2 Hz, 1H), 5.78-5.64 (m,1H), 4.18 (t, J=10.8 Hz, 2H), 4.10-3.99 (m, 2H), 3.74 (dd, J=66.1, 14.7Hz, 3H), 3.17-2.97 (m, 1H), 2.77 (d, J=22.1 Hz, 4H), 2.36 (s, 4H),2.21-2.02 (m, 3H), 1.96 (d, J=21.9 Hz, 3H), 1.86-1.65 (m, 1H), 1.59-1.36(m, 2H), 1.13 (d, J=6.3 Hz, 4H), 1.06 (q, J=6.5 Hz, 1H), 0.92 (s, 1H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₆H₄₃ClF₂N₄O₅S: 717.26; found:716.77.

Example 322

Example 322 was synthesized in the same manner as Example 75 using(1R,3R)-3-methoxycyclopentan-1-amine hydrochloride and Example 109. 1HNMR (400 MHz, DMSO-d6) δ 7.65 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5, 2.4Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.03 (dd, J=8.1, 1.8 Hz, 1H), 6.94 (d,J=8.1 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 5.86 (dt, J=14.4, 6.8 Hz, 1H),5.49 (dd, J=15.2, 8.9 Hz, 1H), 4.20-3.87 (m, 4H), 3.84-3.53 (m, 8H),3.24 (s, 4H), 3.13 (s, 3H), 3.02 (dd, J=15.3, 10.4 Hz, 1H), 2.89-2.60(m, 2H), 2.44-2.30 (m, 2H), 2.29-2.05 (m, 2H), 2.04-1.56 (m, 9H), 1.39(td, J=17.2, 14.6, 9.7 Hz, 1H), 1.02 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₉H₅₁ClN₄O₆S: 739.32; found: 738.81.

Example 323 was synthesized in a manner similar to Example 244 using106-4 instead of 240-1 and using 3,3-difluoroazetidin hydrochlorideinstead of 3-methoxyazetidine hydrochloride. 1H NMR (400 MHZ,Acetone-d6) δ 7.77 (d, J=8.6 Hz, 1H), 7.28-7.20 (m, 1H), 7.17-6.92 (m,4H), 6.05-5.88 (m, 1H), 5.58 (dd, J=15.3, 9.0 Hz, 1H), 4.36 (t, J=12.5Hz, 4H), 4.12 (d, J=12.1 Hz, 1H), 4.08 (d, J=12.0 Hz, 1H), 3.88 (d,J=15.1 Hz, 1H), 3.82-3.61 (m, 2H), 3.54 (d, J=13.5 Hz, 1H), 3.35 (d,J=14.2 Hz, 1H), 3.21 (s, 3H), 3.15 (dd, J=15.4, 10.3 Hz, 1H), 2.89-1.53(m, 15H), 1.53-1.38 (m, 1H), 1.13 (d, J=6.6 Hz, 3H). LCMS: 717.5.

Example 324

Example 324 was synthesized in a manner similar to Example 244 using106-4 instead of 240-1 and using 1,1-difluoro-5-azaspiro[2.3]hexanehydrochloride instead of 3-methoxyazetidine hydrochloride. 1H NMR (400MHz, Acetone-d6) δ 7.77 (d, J=8.6 Hz, 1H), 7.25 (dd, J=8.5, 2.4 Hz, 1H),7.14 (d, J=2.4 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 7.01 (d, J=1.8 Hz, 1H),6.97 (d, J=8.1 Hz, 1H), 5.98 (dt, J=14.1, 6.6 Hz, 1H), 5.58 (dd, J=15.3,8.9 Hz, 1H), 4.45-3.94 (m, 6H), 3.89 (d, J=15.1 Hz, 1H), 3.80-3.67 (m,2H), 3.58-3.40 (m, 1H), 3.35 (d, J=14.2 Hz, 1H), 3.21 (s, 3H), 3.15 (dd,J=15.4, 10.4 Hz, 1H), 2.96-0.77 (m, 18H), 1.14 (d, J=6.5 Hz, 3H). LCMS:742.9.

Example 325

Example 325 was synthesized in a manner similar to Example 214 usingIntermediate 359-4 instead of 106-4. 1H NMR (400 MHz, Acetone-d6) δ 7.79(d, J=8.5 Hz, 1H), 7.51 (s, 1H), 7.41-7.32 (m, 2H), 7.25 (dd, J=8.5, 2.3Hz, 1H), 7.15 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.35 (s, 1H), 6.09-5.97(m, 1H), 5.87 (dd, J=15.8, 6.2 Hz, 1H), 4.96 (d, J=14.5 Hz, 1H), 4.75(d, J=14.5 Hz, 1H), 4.32-3.42 (m, 12H), 3.39 (s, 3H), 3.15 (dd, J=15.2,10.5 Hz, 1H), 2.88-1.39 (m, 16H), 1.15 (d, J=6.4 Hz, 3H). LCMS: 777.1.

Example 326

Example 326 was synthesized in a manner similar to Example 214 usingIntermediate 359-4 instead of 106-4 and using(S)-2-(methoxymethyl)oxirane instead of (R)-2-(methoxymethyl)oxirane. 1HNMR (400 MHz, Acetone-d6) δ 7.79 (d, J=8.6 Hz, 1H), 7.55-7.47 (m, 1H),7.39-7.32 (m, 2H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H),6.94 (d, J=8.1 Hz, 1H), 6.35 (s, 1H), 6.10-5.95 (m, 1H), 5.87 (dd,J=15.7, 6.3 Hz, 1H), 4.96 (d, J=14.5 Hz, 1H), 4.75 (d, J=14.6 Hz, 1H),4.35-3.85 (m, 8H), 3.75 (d, J=14.5 Hz, 1H), 3.65 (dd, J=10.4, 5.3 Hz,1H), 3.56 (dd, J=10.4, 4.8 Hz, 1H), 3.45 (d, J=14.4 Hz, 1H), 3.39 (s,3H), 3.15 (dd, J=15.2, 10.5 Hz, 1H), 2.84-1.65 (m, 15H), 1.53-1.42 (m,1H), 1.15 (d, J=6.4 Hz, 3H). LCMS: 777.1.

Example 327

Example 327 was synthesized in a manner similar to Example 229 usingmorpholine instead of (R)-octahydropyrazino[2,1-c][1,4]oxazinedihydrochloride. 1H NMR (400 MHz, Acetone-d6) δ 7.78 (d, J=8.5 Hz, 1H),7.44 (s, 1H), 7.29-7.17 (m, 3H), 7.15 (d, J=2.4 Hz, 1H), 7.00 (d, J=8.0Hz, 1H), 6.32 (s, 1H), 5.95-5.80 (m, 1H), 5.74 (dd, J=15.4, 7.3 Hz, 1H),4.94 (d, J=14.5 Hz, 1H), 4.84 (d, J=14.5 Hz, 1H), 4.67-1.71 (m, 35H),1.55 (d, J=7.0 Hz, 3H), 1.54-1.42 (m, 1H), 1.08-1.00 (m, 3H). LCMS:846.1.

Example 328

Step 1: Preparation of ethyl (1S,2S)-2-formylcyclopropane-1-carboxylate

The reaction mixture of ethylrac-(1S,2S)-2-(hydroxymethyl)cyclopropanecarboxylate (110 mg, 0.76mmol), Dess-Martin Periodinane (388.34 mg, 0.92 mmol) in DCM (4.0 mL)was stirred at rt overnight. The reaction mixture was washed with 1%Na₂S₂O₄, sat. NaHCO₃, extracted with DCM, dried over MgSO₄, filtered,concentrated, and the residue was purified by silica gel column (0-50%EtOAc/hexane) to give the product.

Step 2: Preparation of Ethyl(1S,2S)-2-(morpholinomethyl)cyclopropane-1-carboxylate

To a solution of ethyl (1S,2S)-2-formylcyclopropane-1-carboxylate (100mg, 0.7 mmol) in DCM (3.0 mL) was added morpholine (0.08 mL, 0.93 mmol)at 0° C. Then to the mixture was added sodium triacetoxyborohydride(0.22 g, 1.06 mmol). The reaction mixture was stirred at rt overnight.The reaction mixture was purified by silica gel chromatography (0-100%EtOAc/hexane, then 0-15% DCM/MeOH) to give the product.

Step 3: Preparation of(1S,2S)-2-(morpholinomethyl)cyclopropane-1-carboxylic Acid

The reaction mixture of ethyl (1S,2S)-2-(morpholinomethyl)cyclopropanecarboxylate (80 mg, 0.375 mol), 2 M NaOH (0.38 mL) in MeOH(2 mL) and H₂O (0.5 mL) was heated at 45° C. overnight. The reactionmixture was concentrated, azeotroped with toluene (×3) to removemoisture and go to next step without purification.

Step 4: Preparation of Example 328

The reaction mixture of(1S,2S)-2-(morpholinomethyl)cyclopropane-1-carboxylic acid (60 mg, 0.32mmol), diphenyl phosphoryl azide (94 mg, 0.341 mmol), trimethylamine (35mg, 0.352 mmol) in toluene (1.0 mL) was stirred at 100° C. for 2 h. Thenthe reaction mixture was cooled down to rt. To the mixture was addedExample 109 and the reaction mixture was stirred at 45° C. overnight.The reaction mixture was concentrated, the residue was purified byreserve phase HPLC (10-100% acetonitrile/H₂O, containing 0.1% TFA) togive the product. 1H NMR (400 MHz, Methanol-d4) δ 7.74 (d, J=8.5 Hz,1H), 7.18 (dd, J=8.5, 2.4 Hz, 1H), 7.12 (q, J=2.9, 2.2 Hz, 2H), 6.97 (d,J=2.0 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.01 (dt, J=14.4, 6.8 Hz, 1H),5.59 (dd, J=15.3, 9.0 Hz, 1H), 4.30 (dd, J=14.9, 6.5 Hz, 1H), 4.18-3.99(m, 4H), 3.84 (dd, J=14.0, 8.7 Hz, 3H), 3.80-3.61 (m, 4H), 3.53-3.41 (m,2H), 3.27 (s, 4H), 3.08 (dd, J=15.2, 10.3 Hz, 1H), 2.95-2.61 (m, 4H),2.58-2.29 (m, 4H), 2.28-2.06 (m, 3H), 2.04-1.69 (m, 6H), 1.45 (t, J=12.1Hz, 1H), 1.39-1.23 (m, 2H), 1.12 (dd, J=15.0, 5.6 Hz, 3H), 0.92 (dt,J=7.9, 5.8 Hz, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₁H₅₄ClN₅O₆S:780.35; found: 780.39.

Example 329

Example 329 was synthesized in a manner similar to Example 167 using229-2 instead of 167-2 and using Intermediate 359-4 instead of 106-4. 1HNMR (400 MHz, Acetone-d6) δ 7.77 (d, J=8.6 Hz, 1H), 7.50-6.85 (m, 6H),6.28 (s, 1H), 6.06-5.56 (m, 2H), 4.91 (d, J=14.5 Hz, 1H), 4.71 (d,J=14.5 Hz, 1H), 4.49-2.97 (m, 13H), 2.81-1.13 (m, 19H), 1.13-0.96 (m,3H). LCMS: 777.4.

Example 330

Example 330 was synthesized in the same manner as Example 75 usingExample 109 and 4-(difluoromethoxy)piperidine. 1H NMR (400 MHz,Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H),7.15-7.06 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 5.97(dt, J=14.2, 6.7 Hz, 1H), 5.58 (dd, J=15.2, 9.2 Hz, 1H), 4.44-4.33 (m,2H), 4.12-4.03 (m, 2H), 4.00-3.81 (m, 3H), 3.76 (dd, J=9.3, 3.7 Hz, 1H),3.70-3.55 (m, 2H), 3.28-3.24 (m, 4H), 3.08 (dd, J=15.3, 10.3 Hz, 1H),2.89-2.71 (m, 2H), 2.54-2.42 (m, 2H), 2.39-2.27 (m, 1H), 2.22-2.06 (m,3H), 1.97-1.87 (m, 5H), 1.86-1.62 (m, 6H), 1.51-1.38 (m, 1H), 1.14 (d,J=6.6 Hz, 3H). LCMS-ESI+ (m/z): calcd H+ for C₃₉H₄₉ClF₂N₄O₆S: 775.30;found: 774.79.

Example 331

Example 331 was synthesized in a manner similar to Example 255 using239-3 instead of 255-3. 1H NMR (400 MHz, Acetone-d6) δ 7.79 (d, J=8.5Hz, 1H), 7.61-6.91 (m, 8H), 6.34 (s, 1H), 6.17-5.58 (m, 2H), 4.79 (s,2H), 4.24-2.88 (m, 12H), 4.05 (s, 4H), 3.35 (s, 6H), 2.82-1.25 (m, 18H),1.11-1.03 (m, 3H). LCMS: 835.3.

Example 332

Step 1

To a stirred solution of Example 358 (25 mg, 0.033 mmol) in methanol (5mL) was added 1N of NaOH (1 mL) and stirred at rt for 24 h. 1 N HCl (1mL) was added to the reaction mixture and the reaction mixture wasconcentrated under reduced pressure. Water was added and the mixture wasextracted with dichloromethane. The organic phase was dried overanhydrous magnesium sulfate and the solvent was removed under reducedpressure to give intermediate 332-1.

Step 2

Example 332 was synthesized by coupling intermediate 332-1 with dimethylamine using EDCI/DMAP in DCM. 1H NMR (400 MHz, Chloroform-d) δ 7.75 (d,J=8.5 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.21 (dd, J=8.4, 2.3 Hz, 1H),7.11 (d, J=2.4 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.87 (d, J=1.8 Hz, 1H),5.96 (dt, J=13.8, 6.4 Hz, 1H), 5.59 (dd, J=15.4, 8.1 Hz, 1H), 4.37-4.00(m, 2H), 3.86 (s, 2H), 3.75 (d, J=12.3 Hz, 1H), 3.38-2.90 (m, 5H),2.87-2.66 (m, 1H), 2.45 (s, 2H), 2.29-1.47 (m, 9H), 1.28 (s, 14H), 1.11(d, J=6.7 Hz, 2H), 0.90 (t, J=6.7 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₄₁H₅₀ClN₅O₆S: 776.32; found: 776.12.

Example 333

Example 333 was synthesized in the same manner as Example 362, usingExample 109 and N,N-dimethylazetidin-3-amine dihydrochloride. LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₃₈H₅₀ClN₅O₅S: 724.3294; found: 724.08. ¹H NMR(400 MHz, Methanol-d₄) δ 7.71 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H),7.10 (d, J=2.2 Hz, 1H), 7.07 (dd, J=8.2, 1.9 Hz, 1H), 6.93-6.86 (m, 2H),5.97 (dt, J=14.3, 6.7 Hz, 1H), 5.56 (dd, J=15.2, 9.2 Hz, 1H), 4.39-4.24(m, 3H), 4.24-4.13 (m, 2H), 4.13-3.99 (m, 3H), 3.83 (d, J=15.1 Hz, 1H),3.74 (dd, J=9.2, 3.7 Hz, 1H), 3.69-3.54 (m, 2H), 3.28-3.25 (m, 1H), 3.24(s, 3H), 3.06 (dd, J=15.3, 10.3 Hz, 1H), 2.91 (s, 6H), 2.87-2.69 (m,2H), 2.46 (dd, J=13.0, 7.5 Hz, 2H), 2.32 (p, J=8.9 Hz, 1H), 2.23-2.03(m, 3H), 2.01-1.65 (m, 6H), 1.42 (t, J=12.3 Hz, 1H), 1.12 (d, J=6.5 Hz,3H).

Example 334

Example 334 was synthesized in the same manner as Example 362, usingExample 109 and (R)-octahydropyrazino[2,1-c][1,4]oxazinedihydrochloride. LCMS-ESI+ (m/z): [M+H]⁺ calc'd for C₄₀H₅₂ClN₅O₆S:766.3400; found: 766.10. ¹H NMR (400 MHz, Methanol-d4) δ 7.72 (d, J=8.5Hz, 1H), 7.17 (dd, J=8.5, 2.4 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 7.05 (dd,J=8.1, 1.9 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 5.94(dt, J=14.3, 6.7 Hz, 1H), 5.56 (dd, J=15.2, 9.3 Hz, 1H), 4.57 (s, 2H),4.39 (dd, J=14.9, 6.7 Hz, 1H), 4.20-3.94 (m, 4H), 3.84 (d, J=15.0 Hz,2H), 3.75 (dd, J=9.4, 3.7 Hz, 1H), 3.70-3.60 (m, 2H), 3.61-3.36 (m, 4H),3.30-3.25 (m, 3H), 3.24 (s, 3H), 3.21-3.12 (m, 1H), 3.07 (dd, J=15.4,10.2 Hz, 1H), 2.87-2.69 (m, 3H), 2.54-2.38 (m, 2H), 2.29 (p, J=8.9, 8.4Hz, 1H), 2.23-2.02 (m, 3H), 2.01-1.66 (m, 6H), 1.43 (t, J=12.6 Hz, 1H),1.11 (d, J=6.5 Hz, 3H).

Example 335

Step 1

The reaction mixture of tert-butyl (trans-3-(hydroxymethyl)cyclobutyl)carbamate (368 mg, 1.83 mmol) and N,N-dimethylcarbamoylchloride (0.20 mL, 2.19 mmol) in pyridine was heated at 90° C.overnight. Upon cooling to room temperature, 5 mL of iced water wasadded and the reaction mixture was diluted with EtOAc (70 mL), washedwith water (30 mL), brine, dried and concentrated, and purified bycolumn chromatography using 0-60% EtOAc in hexane to afford intermediate335-1. ¹H NMR (400 MHz, Acetone-d₆) δ 6.27 (s, 1H), 4.21 (m, 1H),4.12-4.00 (m, 2H), 2.92 (s, 3H), 2.86 (s, 3H), 2.54-2.38 (m, 1H),2.21-2.10 (m, 4H), 1.40 (s, 9H).

Step 2

Intermediate 335-2 (130 mg, 0.48 mmol) was dissolved in EtOAc (1 mL) andthen 4 N HCl in dioxane (4 mL) was added. The reaction mixture wasstirred at room temperature for 4 hrs. Nitrogen was bubbled through todrive out the HCl and the solvent was removed to get 335-2. It was usedwithout further purification in next step.

Step 3

Example 335 was synthesized in the same manner as Example 75 usingintermediate 335-2 and Example 109. ¹H NMR (400 MHz, Methanol-d₄) δ 7.67(d, J=9.0 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.06(s, 1H), 6.97 (s, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.03 (d, J=15.4 Hz, 1H),5.57 (dd, J=15.3, 8.7 Hz, 1H), 4.34-4.27 (m, 1H), 4.20 (d, J=13.9 Hz,1H), 4.11 (d, J=6.8 Hz, 2H), 4.03 (s, 2H), 3.79 (dd, J=23.6, 12.1 Hz,3H), 3.68 (d, J=14.1 Hz, 1H), 3.27 (s, 3H), 3.06-3.00 (m, 1H), 2.94 (s,3H), 2.92 (s, 3H), 2.77 (d, J=18.8 Hz, 2H), 2.56 (s, 2H), 2.45 (d,J=18.0 Hz, 2H), 2.29-2.21 (m, 3H), 2.15 (q, J=11.8, 10.2 Hz, 4H), 2.03(d, J=7.4 Hz, 2H), 1.95 (d, J=11.5 Hz, 2H), 1.79 (d, J=5.1 Hz, 2H), 1.39(d, J=13.8 Hz, 2H), 1.11 (d, J=6.2 Hz, 3H). LCMS-ESI⁺[M+H]⁺ calc'd forC₄₁H₅₄ClN₅O₇S: 796.34; found: 795.87.

Example 336

Step 1

The reaction mixture of tert-butyl (cis-3-(hydroxymethyl)cyclobutyl)carbamate (515 mg, 2.56 mmol) and ACV-dimethylcarbamoyl chloride (0.31mL, 3.33 mmol) in pyridine was heated at 90° C. overnight. Upon coolingto room temperature, 5 mL of iced water was added and the reactionmixture was diluted with ethyl ether (70 mL), washed with water (30 mL),brine, dried and concentrated, and purified by column chromatographyusing 30-80% EtOAc in hexane to afford intermediate 336-1. ¹H NMR (400MHz, Acetone-d₆) δ 6.24 (s, 1H), 3.98 (m, 3H), 2.90 (s, 3H), 2.87 (s,3H), 2.34 (m, 2H), 2.29-2.19 (m, 1H), 1.78 (m, 2H), 1.39 (s, 9H).

Step 2: Preparation of Intermediate 336-2

Intermediate 336-1 (165 mg, 0.61 mmol) was dissolved in EtOAc (1 mL) andthen 4 N HCl in dioxane (4 mL) was added. The reaction mixture wasstirred at room temperature for 4 hrs. Nitrogen was bubbled through todrive out the HCl and the solvent was removed to get 336-2. It was usedwith no further purification in next step.

Step 3

Example 336 was synthesized in the same manner as Example 75 usingintermediate 336-2 and Example 109. ¹H NMR (400 MHz,Methanol-d₄/Chloroform-d (3/1)) δ 7.66 (d, 1H), 7.21 (d, J=8.1 Hz, 1H),7.05 (d, J=2.1 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.97 (s, 1H), 6.85 (d,J=8.2 Hz, 1H), 6.03 (dd, J=14.6, 7.6 Hz, 1H), 5.59 (dd, J=15.4, 8.7 Hz,1H), 4.20-4.09 (m, 2H), 4.05-3.99 (m, 4H), 3.79 (dd, J=19.0, 12.5 Hz,3H), 3.71-3.63 (m, 1H), 3.28 (s, 3H), 3.03 (dd, J=15.1, 9.7 Hz, 1H),2.93 (s, 3H), 2.91 (s, 3H), 2.85-2.73 (m, 2H), 2.55-2.39 (m, 5H),2.35-2.28 (m, 1H), 2.21 (d, J=17.3 Hz, 2H), 2.07 (d, J=13.7 Hz, 2H),1.96 (d, J=5.2 Hz, 1H), 1.77 (dd, J=19.6, 9.7 Hz, 6H), 1.41-1.32 (m,2H), 1.12 (d, J=6.3 Hz, 3H). LCMS-ESI+[M+H]⁺ calc'd for C₄₁H₅₄ClN₅O₇S:796.34; found:795.84.

Example 337

Step 1

A vigorously stirred mixture of methyl 5-formyl-1H-pyrrole-3-carboxylate(400 mg, 2.61 mmol), 1-bromo-2-m ethoxy ethane (982 μL, 10.5 mmol), andpotassium carbonate (722 mg, 5.22 mmol) in acetonitrile (8.0 mL) 80° C.After 210 min, the reaction mixture was allowed to cool to roomtemperature, was filtered through celite, and was concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 45% ethyl acetate in hexanes) to give337-1.

Step 2

Sodium borohydride (274 mg, 7.24 mmol) was added to a stirred solutionof 337-1 (510 mg, 2.41 mmol) in methanol (10 mL) and tetrahydrofuran(5.0 mL) at 0° C., and the resulting mixture was warmed to roomtemperature. After 20 min, ethyl acetate (125 mL) was added. The organiclayer was washed with a mixture of water and brine (1:1 v:v, 2×80 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(6.0 mL), and the resulting mixture was stirred and cooled to −20° C.Potassium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran,4.11 mL, 4.1 mmol) was added via syringe. After 10 min, iodomethane (342μL, 5.48 mmol) was added via syringe, and the resulting mixture waswarmed to room temperature. After 60 min, saturated aqueous ammoniumchloride solution (5 mL), diethyl ether (65 mL), and ethyl acetate (65mL) were added sequentially. The organic layer was washed sequentiallywith a mixture of water and brine (2:1 v:v, 100 mL) and water (100 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (0 to 45% ethyl acetate in hexanes) to give337-2.

Step 3

Aqueous sodium hydroxide solution (2.0 M, 3.18 mL, 6.4 mmol) was addedvia syringe to a stirred solution of 337-3 (248 mg, 1.09 mmol) intetrahydrofuran (1.0 mL) and methanol (3.0 mL) at room temperature, andthe resulting mixture was heated to 70° C. After 2 h, the resultingmixture was allowed to cool to room temperature, and aqueous hydrogenchloride solution (2.0 M, 3.5 mL), water (5 mL), and brine (20 mL) wereadded sequentially. The aqueous layer was extracted sequentially withdichloromethane (2×) and ethyl acetate (30 mL), and the combined organiclayers were dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to give 337-3.

Step 4

3-(((Ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (6.7 mg, 35 μmol) was added to a stirred mixture of 106-4(7.0 mg, 12 μmol), X-3 (5.0 mg, 23 μmol), and 4-(dimethylamino)pyridine(4.3 mg, 35 μmol) in dichloromethane (1.0 mL) at room temperature, andthe resulting mixture was heated to 45° C. After 60 min, ethyl acetate(30 mL) was added. The organic layer was washed sequentially withaqueous citric acid solution (5% wt., 30 mL) and water (30 mL), driedover magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (0 to 10% methanol in dichloromethane) to give impure Example337. The impure product was purified on C18-reverse phase silica gel (0to 100% acetonitrile in water) to give Example 337. 1H NMR (400 MHz,Acetone-d6) δ 7.79 (d, J=8.6 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.27-7.21(m, 2H), 7.14 (s, 1H), 7.02-6.79 (m, 1H), 6.57 (s, 1H), 6.32-6.06 (m,1H), 5.75-5.44 (m, 1H), 4.72-3.02 (m, 14H), 3.32 (s, 3H), 3.27 (s, 3H),3.24 (s, 3H), 2.86-1.18 (m, 16H), 1.13 (d, J=6.6 Hz, 3H). LCMS: 815.1(M+Na)+.

Example 338

Example 338 was synthesized in a manner similar to Example 337 using1-bromo-3-methoxypropane instead of 1-bromo-2-m ethoxy ethane. 1H NMR(400 MHz, Acetone-d6) δ 7.79 (d, J=8.6 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H),7.30-7.18 (m, 2H), 7.13 (d, J=2.3 Hz, 1H), 7.01-6.76 (m, 1H), 6.52 (s,1H), 6.37-6.06 (m, 1H), 5.69-5.46 (m, 1H), 4.57-2.97 (m, 14H), 3.31 (s,3H), 3.26 (s, 3H), 3.24 (s, 3H), 2.96-1.18 (m, 18H), 1.12 (d, J=6.6 Hz,3H). LCMS: 829.1 (M+Na)+.

Example 339

Example 339 was prepared in a similar manner to Example 106 using5-(methoxymethyl)-4-methylfuran-2-carboxylic acid and Example 109. ¹HNMR (400 MHz, Acetone-d₆) δ 7.76 (d, J=8.5 Hz, 1H), 7.28-7.18 (m, 2H),7.11 (d, J=8.8 Hz, 3H), 6.93 (d, J=8.1 Hz, 1H), 6.08 (br s, 1H), 5.61(dd, J=15.4, 8.5 Hz, 1H), 4.43 (s, 2H), 4.16-3.99 (m, 2H), 3.88 (d,J=14.9 Hz, 1H), 3.73 (d, J=13.1 Hz, 2H), 3.38 (d, J=14.6 Hz, 2H), 3.33(s, 3H), 3.22 (s, 3H), 3.20-3.10 (m, 2H) 2.87-2.69 (m, 2H), 2.47 (s,4H), 2.25 (d, J=14.5 Hz, 4H), 2.11 (s, 3H), 2.00-1.66 (m, 5H), 1.14 (d,J=6.2 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₄₉ClN₃O₇S: 750.29;found: 749.94.

Example 340

Example 340 was synthesized in the same manner as Example 281 using1-methyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid and Example 109. 1HNMR (400 MHz, DMSO-d6) δ 7.66 (d, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.27 (dd,J=8.5, 2.4 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.95(s, 1H), 6.90 (d, J=8.1 Hz, 1H), 5.96 (dt, J=14.4, 6.8 Hz, 1H), 5.49(dd, J=15.2, 8.7 Hz, 1H), 4.15-3.88 (m, 3H), 3.78 (t, J=16.6 Hz, 2H),3.70-3.52 (m, 8H), 3.22 (d, J=14.2 Hz, 1H), 3.14 (s, 3H), 3.01 (dd,J=15.2, 10.5 Hz, 1H), 2.88-2.60 (m, 2H), 2.46-2.20 (m, 3H), 2.18-2.07(m, 1H), 2.05-1.91 (m, 4H), 1.90-1.78 (m, 2H), 1.77-1.55 (m, 4H), 1.35(s, 3H), 1.01 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₉H₄₉ClN₄O₆S: 737.31; found: 736.75.

Example 341

Example 341 was synthesized in the same manner as Example 281 using5-oxaspiro[2.4]heptane-1-carboxylic acid and Example 109. Mixture of twoisomers separated and stereo chemistry arbitrarily assigned but notabsolute. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J=8.5 Hz, 1H), 7.27 (dd,J=8.5, 2.4 Hz, 1H), 7.16 (dd, J=14.5, 5.3 Hz, 2H), 6.97 (d, J=12.0 Hz,2H), 6.89 (d, J=8.2 Hz, 1H), 6.55 (s, 1H), 6.07-5.85 (m, 1H), 5.49 (dd,J=15.3, 8.7 Hz, 1H), 4.17-4.01 (m, 2H), 3.95 (d, J=12.2 Hz, 1H),3.91-3.72 (m, 3H), 3.69-3.47 (m, 3H), 3.27-3.17 (m, 6H), 3.14 (d, J=1.8Hz, 3H), 3.01 (dd, J=15.2, 10.5 Hz, 1H), 2.87-2.58 (m, 3H), 2.44-2.31(m, 2H), 2.31-2.06 (m, 1H), 2.00 (d, J=14.3 Hz, 1H), 1.74 (ddt, J=55.6,20.6, 8.8 Hz, 6H), 1.36 (d, J=10.0 Hz, 1H), 1.08 (t, J=6.9 Hz, 1H), 1.00(dd, J=6.8, 4.2 Hz, 3H), 0.70 (dt, J=21.3, 5.1 Hz, 1H. LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₉H₄₉ClN₄O₆S: 737.31; found: 736.87.

Example 342

Example 342 was synthesized in the same manner as Example 281 using5-oxaspiro[2.4]heptane-1-carboxylic acid and Example 109. Stereochemistry arbitrarily assigned but not absolute. 1H NMR (400 MHz,DMSO-d6) δ 7.66 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.5, 2.4 Hz, 1H), 7.16(dd, J=13.4, 5.2 Hz, 2H), 6.98 (d, J=16.0 Hz, 2H), 6.89 (dd, J=8.2, 2.5Hz, 1H), 6.55 (s, 1H), 5.96 (s, 1H), 5.50 (dd, J=15.3, 8.6 Hz, 1H), 4.04(d, J=12.3 Hz, 2H), 3.95 (d, J=12.3 Hz, 1H), 3.90-3.71 (m, 3H),3.71-3.60 (m, 2H), 3.59-3.46 (m, 2H), 3.22 (d, J=14.5 Hz, 4H), 3.14 (d,J=1.8 Hz, 3H), 3.01 (dd, J=15.2, 10.5 Hz, 1H), 2.87-2.58 (m, 4H),2.44-2.32 (m, 2H), 2.20 (d, J=54.6 Hz, 1H), 1.99 (d, J=14.0 Hz, 2H),1.91-1.57 (m, 5H), 1.40 (d, J=13.8 Hz, 1H), 1.12-0.93 (m, 4H), 0.70 (dt,J=20.0, 5.1 Hz, 1H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₉H₄₉ClN₄O₆S:737.31; found: 736.87.

Example 343

Step 1: Preparation of Intermediate 343-1

To a stirred solution of intermediate 359-2 (1.4 g, 1.83 mmol) inmethanol (20 mL) was added water (2 mL), K₂CO₃ (1.7 g, 18.3 mmol) andstirred at 60° C. for 24 hrs. More water was added and the mixture wasextracted with dichloromethane. The organic phase was dried overanhydrous magnesium sulfate and the solvent was removed under reducedpressure.

Step 2

To a stirred solution of Intermediate 184-1 (0.72 g, 1.1 mmol) in DCM (5mL) was added 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (200 mg,1.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (397 mg,2.5 mmol) and 4-(dimethylamino)pyridine (312 mg, 2.5 mmol). The reactionmixture was stirred at room temperature for 24 hr. Then the reactionmixture was diluted with DCM, and washed with 1 N HCl and brine. Theorganic phase was dried over MgSO₄, filtered, concentrated, and purifiedon normal phase chromatography 0-10% DCM/MeOH to yield intermediate343-2.

Step 3

To a stirred solution of intermediate 343-2 (100 mg, 0.13 mmol),Hoveyda-Grubbs II (33 mg, 0.039 mmol) and TFA (44 mg, 0.39 mmol) in1,2-dichloroethane (38 mL) was degassed with argon. The reaction mixturewas stirred at 60° C. overnight. The reaction mixture was concentratedand purified on reversed phase chromatography 0.1% TFA 70-95%acetonitrile to give Example 343. 1H NMR (400 MHz, Chloroform-d)δ7.84-7.70 (m, 2H), 7.52 (dd, J=8.2, 1.9 Hz, 1H), 7.39 (d, J=1.9 Hz,1H), 7.20 (dd, J=8.5, 2.3 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 6.95 (d,J=8.3 Hz, 1H), 5.64 (t, J=10.0 Hz, 1H), 5.49 (td, J=10.8, 4.1 Hz, 1H),4.75 (d, J=8.4 Hz, 1H), 4.48 (dt, J=7.7, 3.9 Hz, 1H), 4.11 (d, J=18.9Hz, 4H), 3.92 (d, J=15.1 Hz, 1H), 3.83 (s, 3H), 3.49 (d, J=14.7 Hz, 1H),3.28 (dd, J=15.3, 10.1 Hz, 2H), 2.93-2.53 (m, 4H), 2.39 (s, 2H),2.18-1.72 (m, 10H), 1.48 (d, J=6.9 Hz, 2H), 1.40 (d, J=7.2 Hz, 3H), 1.28(s, 2H), 0.93-0.72 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₈H₄₆ClN₅O₆S: 736.29; found: 736.16.

Example 344

Example 344 was synthesized in a manner similar to Example 344 usingIntermediate 359-4 instead of 106-4. 1H NMR (400 MHz, Acetone-d6) δ 7.79(d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.30-7.17 (m, 3H), 7.15 (d, J=2.3 Hz,1H), 7.00 (d, J=8.0 Hz, 1H), 6.30 (s, 1H), 5.95-5.81 (m, 1H), 5.74 (dd,J=15.1, 7.2 Hz, 1H), 4.92 (d, J=14.5 Hz, 1H), 4.80-4.67 (m, 1H),4.44-3.31 (m, 12H), 3.39 (s, 3H), 3.19 (dd, J=15.2, 8.7 Hz, 1H),3.13-1.40 (m, 15H), 1.55 (d, J=7.2 Hz, 3H), 1.11-0.99 (m, 3H). LCMS:791.0.

Example 345

Example 345 was synthesized in a manner similar to Example 214 usingIntermediate 359-4 instead of 106-4 and using(S)-2-(methoxymethyl)oxirane instead of (R)-2-(methoxymethyl)oxirane. 1HNMR (400 MHz, Acetone-d6) δ 7.79 (d, J=8.5 Hz, 1H), 7.44 (s, 1H),7.29-7.17 (m, 3H), 7.15 (d, J=2.3 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.31(s, 1H), 5.96-5.82 (m, 1H), 5.74 (dd, J=15.2, 7.3 Hz, 1H), 4.92 (d,J=14.4 Hz, 1H), 4.73 (d, J=14.4 Hz, 1H), 4.47-3.33 (m, 12H), 3.39 (s,3H), 3.19 (dd, J=15.1, 8.7 Hz, 1H), 3.05-1.41 (m, 15H), 1.56 (d, J=7.1Hz, 2H), 1.11-0.98 (m, 3H). LCMS: 791.0.

Example 346

Example 346 was prepared in a similar manner as Example 75 using3-(methoxymethyl)azetidine hydrochloride, triethylamine and Example 109.1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5, 2.4Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.07 (dd, J=8.2, 1.8 Hz, 1H), 6.91 (d,J=8.1 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 5.90 (dt, J=14.4, 6.8 Hz, 1H),5.49 (dd, J=15.2, 8.8 Hz, 1H), 4.17-3.87 (m, 4H), 3.83-3.68 (m, 2H),3.68-3.53 (m, 2H), 3.51 (s, 6H), 3.28 (s, 3H), 3.20 (d, J=14.1 Hz, 1H),3.13 (s, 4H), 3.01 (dd, J=15.3, 10.4 Hz, 1H), 2.87-2.59 (m, 4H),2.45-2.31 (m, 2H), 2.29-2.06 (m, 2H), 2.04-1.57 (m, 7H), 1.45-1.32 (m,1H), 1.01 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): LCMS-ESI+ (m/z): [M+H]+calcd for C₃₈H₄₉ClN₄O₆S: 725.31; found: 725.06.

Example 347

Example 347 was prepared in a similar manner to Example 75 using(S)-3-methoxypyrrolidine, triethylamine and Example 109. 1H NMR (400MHz, DMSO-d6) δ 7.65 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5, 2.4 Hz, 1H),7.18 (d, J=2.3 Hz, 1H), 7.03 (dd, J=8.1, 1.8 Hz, 1H), 6.94 (d, J=8.1 Hz,1H), 6.84 (d, J=2.0 Hz, 1H), 5.86 (dt, J=14.4, 6.8 Hz, 1H), 5.49 (dd,J=15.2, 8.9 Hz, 1H), 4.20-3.87 (m, 4H), 3.84-3.53 (m, 8H), 3.24 (s, 4H),3.13 (s, 3H), 3.02 (dd, J=15.3, 10.4 Hz, 1H), 2.89-2.60 (m, 2H),2.44-2.30 (m, 2H), 2.29-2.05 (m, 2H), 2.04-1.56 (m, 8H), 1.39 (td,J=17.2, 14.6, 9.7 Hz, 1H), 1.02 (d, J=6.8 Hz, 3H). LCMS-ESI+(m/z):[M+H]+ calcd for C₃₈H₄₉ClN₄O₆S: 725.31; found: 725.00.

Example 348

Example 348 was synthesized in the same manner as Example 362, usingExample 109 and 1-(azetidin-3-yl)imidazole dihydrochloride. LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₃₉H₄₇ClN₆O₅S: 747.3090; found: 747.13. ¹H NMR(400 MHz, Methanol-d₄) δ 9.16 (s, 1H), 7.94 (t, J=1.8 Hz, 1H), 7.72 (d,J=8.5 Hz, 1H), 7.68 (t, J=1.8 Hz, 1H), 7.16 (dd, J=8.4, 2.3 Hz, 1H),7.12-7.05 (m, 2H), 6.96-6.87 (m, 2H), 5.97 (dt, J=14.3, 6.5 Hz, 1H),5.57 (dd, J=15.2, 9.1 Hz, 1H), 5.35 (td, J=8.0, 4.0 Hz, 1H), 4.68-4.51(m, 2H), 4.43-4.20 (m, 3H), 4.13-4.00 (m, 2H), 3.84 (d, J=15.1 Hz, 1H),3.75 (dd, J=9.2, 3.6 Hz, 1H), 3.70-3.57 (m, 2H), 3.28-3.26 (m, 1H), 3.24(s, 3H), 3.07 (dd, J=15.2, 10.3 Hz, 1H), 2.88-2.68 (m, 2H), 2.52-2.40(m, 2H), 2.32 (p, J=8.6 Hz, 1H), 2.24-2.03 (m, 3H), 2.00-1.67 (m, 6H),1.43 (t, J=12.7 Hz, 1H), 1.14 (d, J=6.5 Hz, 3H).

Example 349 was synthesized in the same manner as Example 362, usingExample 109 and 4-(azetidin-3-yl)morpholine dihydrochloride. LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₄₀H₅₂ClN₅O₆S: 766.3400; found: 765.95. ¹H NMR(400 MHz, Methanol-d4) δ 7.70 (d, J=8.5 Hz, 1H), 7.18-7.03 (m, 3H),6.97-6.82 (m, 2H), 5.96 (dt, J=14.1, 6.6 Hz, 1H), 5.57 (dd, J=15.2, 9.1Hz, 1H), 4.39-4.15 (m, 5H), 4.11-3.99 (m, 4H), 3.93 (s, 3H), 3.83 (d,J=15.2 Hz, 1H), 3.74 (dd, J=9.2, 3.6 Hz, 1H), 3.69-3.59 (m, 2H),3.31-3.25 (m, 5H), 3.24 (s, 3H), 3.07 (dd, J=15.3, 10.3 Hz, 1H),2.87-2.68 (m, 2H), 2.53-2.40 (m, 2H), 2.33 (p, J=8.3, 7.4 Hz, 1H),2.23-2.04 (m, 3H), 2.01-1.67 (m, 6H), 1.42 (t, J=12.6 Hz, 1H), 1.13 (d,J=6.5 Hz, 3H).

Example 350

Example 350 was synthesized in the same manner as Example 75 usingExample 109 and (3R)-3-methoxypyrrolidine; hydrochloride and DIEA. 1HNMR (400 MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5,2.3 Hz, 1H), 7.14-7.08 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.90 (s, 1H),6.01-5.91 (m, 1H), 5.58 (dd, J=15.2, 9.2 Hz, 1H), 4.39-4.29 (m, 1H),4.13-4.05 (m, 2H), 4.05-4.00 (m, 1H), 3.85 (d, J=15.4 Hz, 1H), 3.76 (dd,J=9.3, 3.6 Hz, 1H), 3.71-3.49 (m, 5H), 3.48-3.39 (m, 1H), 3.36 (s, 3H),3.26 (s, 3H), 3.13-3.03 (m, 1H), 2.88-2.71 (m, 2H), 2.54-2.43 (m, 2H),2.39-2.28 (m, 1H), 2.24-1.67 (m, 12H), 1.50-1.39 (m, 1H), 1.18-1.11 (m,3H). LCMS-ESI+ (m/z): calcd H+ for C₃₈H₄₉ClN₄O₆S: 725.31; found: 724.95.

Example 351

Example 351 was synthesized in the same manner as Example 75 using3-(difluoromethyl)azetidine and Example 109. ¹H NMR (400 MHz,Methanol-d₄) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H),7.11 (dd, J=8.4, 2.0 Hz, 2H), 6.96-6.89 (m, 2H), 6.32-5.87 (m, 2H), 5.58(dd, J=15.2, 9.1 Hz, 1H), 4.33 (dd, J=14.9, 6.4 Hz, 1H), 4.24-3.93 (m,5H), 3.85 (d, J=15.2 Hz, 1H), 3.76 (dd, J=9.2, 3.6 Hz, 1H), 3.65 (m,2H), 3.27 (m, 2H), 3.26 (s, 3H), 3.18-3.00 (m, 2H), 2.92-2.71 (m, 2H),2.55-2.29 (m, 3H), 2.25-2.07 (m, 3H), 1.97-1.70 (m, 5H), 1.44 (t, J=12.2Hz, 1H), 1.15 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₇H₄₅ClF₂N₄O₅S: 731.3; found: 730.8.

Example 352

Example 352 was synthesized in the same manner as Example 362, usingExample 109 and 3-(azetidin-3-yloxy)pyridine dihydrochloride. LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₄₁H₄₈ClN₅O₆S: 774.3087; found: 773.82. ¹H NMR(400 MHz, Methanol-d₄) δ 8.41 (d, J=16.0 Hz, 2H), 7.76 (dd, J=27A, 11.3Hz, 3H), 7.16 (dd, J=8.5, 2.3 Hz, 1H), 7.13-7.03 (m, 2H), 6.95-6.86 (m,2H), 5.95 (dt, J=14.3, 6.7 Hz, 1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 5.20(s, 1H), 4.51 (s, 2H), 4.32 (dd, J=14.9, 6.3 Hz, 1H), 4.14-4.01 (m, 4H),3.83 (d, J=15.1 Hz, 1H), 3.74 (dd, J=9.2, 3.7 Hz, 1H), 3.68-3.55 (m,2H), 3.29-3.25 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J=15.2, 10.3 Hz, 1H),2.87-2.66 (m, 2H), 2.54-2.38 (m, 2H), 2.32 (q, J=9.0 Hz, 1H), 2.23-2.04(m, 3H), 2.00-1.65 (m, 6H), 1.42 (t, J=12.7 Hz, 1H), 1.13 (d, J=6.5 Hz,3H).

Example 353

Step 1

To a stirred solution of Intermediate 343-2 (145 mg, 0.19 mmol) in DCM(5 mL) in ice-water bath was added Dess-Martin periodinane (241 mg, 0.56mmol) in one portion. The reaction was warmed at room temperature andstirred for 30 min. Reaction mixture was diluted with DCM, and washedwith 1 N HCl and brine. The organic phase was dried over MgSO₄,filtered, concentrated and purified on reversed phase chromatography0.1% TFA 70-95% acetonitrile to give intermediate 353-1.

Step 2

To a stirred solution of intermediate 353-1 (50 mg, 0.06 mmol),Hoveyda-Grubbs II (16.6 mg, 0.020 mmol) and TFA (22 mg, 0.19 mmol) in1,2-dichloroethane (19 mL) was degassed with argon. The reaction mixturewas stirred at 60° C. overnight. The reaction mixture was concentratedand purified on normal phase chromatography 0-10% DCM/MeOH to yieldintermediate 353-2.

Step 3

To a stirred solution of intermediate 174-2 (16 mg, 0.022 mmol) inmethanol (2 mL) and CeCl₃ (16 mg, 0.065 mmol) at 0° C. was added insmall portions NaBH₄ (1.2 mg, 0.033 mmol), and stirred at 0° C. for 1 h.The mixture was diluted with a 10% aqueous ammonium chloride solution.The organic solvent was removed using an evaporator. The remainingaqueous solution was subjected to two extractions with ethyl acetate.The organic layer was washed with saturated brine, then dried oversodium sulfate and then concentrated. The residue was purified onreversed phase chromatography 0.1% TFA 70-95% acetonitrile to giveExample 353. ¹H NMR (400 MHz, Chloroform-d) δ 7.84-7.72 (m, 2H), 7.63(s, 1H), 7.33 (d, J=7.7 Hz, 2H), 7.21 (dd, J=8.5, 2.4 Hz, 1H), 7.10 (d,J=2.3 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 5.58 (dd, J=15.5, 7.5 Hz, 1H),5.51-5.40 (m, 1H), 4.11 (d, J=15.5 Hz, 4H), 3.96 (d, J=16.1 Hz, 1H),3.84-3.68 (m, 3H), 3.26 (d, J=14.3 Hz, 1H), 3.08-2.90 (m, 1H), 2.85-2.72(m, 2H), 2.59 (s, 2H), 2.09 (d, J=15.0 Hz, 5H), 1.98-1.67 (m, 4H), 1.56(d, J=7.3 Hz, 3H), 1.28 (m, 2H), 1.02 (d, J=6.9 Hz, 2H), 0.92-0.78 (m,3H), 0.72-0.45 (m, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C₃₈H₄₆ClN₅O₆S:736.29; found: 736.16.

Example 354

Example 354 was synthesize in the same manner as Example 182, using3-(difluoromethoxy)azetidine instead ofrac-(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropan-1-amine. 1H NMR (400MHz, Methanol-d4) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.6, 2.4 Hz,1H), 7.11 (dd, J=8.2, 2.0 Hz, 2H), 7.00-6.88 (m, 2H), 6.49 (t, J=74.0Hz, 1H), 5.97 (dt, J=14.4, 6.8 Hz, 1H), 5.58 (dd, J=15.2, 9.2 Hz, 1H),4.32 (dd, J=14.7, 6.6 Hz, 2H), 4.09 (d, J=1.8 Hz, 3H), 3.85 (d, J=15.2Hz, 1H), 3.76 (dd, J=9.2, 3.6 Hz, 1H), 3.72-3.54 (m, 3H), 3.26 (s, 3H),3.08 (dd, J=15.2, 10.3 Hz, 2H), 2.88-2.67 (m, 3H), 2.55-2.43 (m, 2H),2.35 (q, J=8.9 Hz, 2H), 2.25-2.08 (m, 3H), 1.96 (s, 3H), 1.79 (tt,J=17.5, 9.5 Hz, 3H), 1.45 (t, J=12.5 Hz, 1H), 1.15 (d, J=6.6 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₇H₄₅ClF₂N₄O₆S: 747.27; found:746.28.

Example 355

Example 355 was synthesized in the same manner as Example 75 using3-(2,2-difluoroethyl)azetidine and Example 109. ¹H NMR (400 MHz,Methanol-d₄) δ 7.75 (d, J=8.5 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz, 1H),7.12 (d, J=2.3 Hz, 2H), 6.92 (d, J=2.6 Hz, 2H), 6.02-5.93 (m, 1H), 5.58(dd, J=15.2, 9.0 Hz, 1H), 4.30 (dd, J=14.8, 6.4 Hz, 1H), 4.21 (br, 3H),4.08 (d, J=2.5 Hz, 2H), 3.97-3.70 (m, 2H), 3.73-3.57 (m, 2H), 3.3-3.26(m, 2H), 3.26 (s, 2H), 3.17-3.02 (m, 1H), 2.97-2.75 (m, 4H), 2.56-2.43(m, 1H), 2.35 (q, J=9.3, 8.2 Hz, 1H), 2.28-2.07 (m, 3H), 2.01-1.78 (m,4H), 1.45 (t, J=12.7 Hz, 1H), 1.15 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₈H₄₇ClF₂N₄O₅S: 745.3; found: 744.8.

Example 356

Step 1: Synthesis of 356-1

To the mixture of ethyl 3-hydroxy-1-methyl-pyrazole-4-carboxylate (200.0mg, 1.18 mmol) and 1,3-dioxolan-2-ylmethanol (159 mg, 1.53 mmol) in THF(5.0 mL) at room temperature was added tri-N-butylphosphine (309 mg,1.53 mmol) followed by diisopropyl azodicarboxylate (309 mg, 1.53 mmol)dropwise. The resulting mixture was stirred at room temperature for 3hours and then heated at 70° C. for overnight. The reaction was cooledto room temperature, concentrated, purified by combiflash (12 g silicagel, 0-50% EtOAc/Hexanes). The desired fractions were concentrated togive the title compound. 1H NMR (400 MHz, Chloroform-d) δ 7.80 (s, 1H),5.24 (t, J=3.9 Hz, 1H), 4.51 (d, J=3.9 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H),4.07-3.99 (m, 2H), 3.99-3.93 (m, 2H), 3.76 (s, 3H), 1.37 (t, J=7.1 Hz,3H).

Step 2: Synthesis of 356-2

Intermediate 356-1 (44.0 mg, 0.172 mmol) in EtOH and treated with 1NNaOH (0.21 mL, 0.21 mmol) at 60° C. for 1 hr. Additional 1 N NaOH (1.72mL, 1.72 mmol) was added, the reaction mixture was heated continuouslyfor 5 hrs. The reaction was cooled to room temperature, concentrated,diluted with EtOAc, washed with 1 N HCl, brine, dried over sodiumsulfate, filtered and concentrated to give 356-2. 1H NMR (400 MHz,Chloroform-d) δ 7.85 (s, 1H), 5.24 (t, J=3.9 Hz, 1H), 4.51 (d, J=3.9 Hz,2H), 4.08-3.91 (m, 4H), 3.75 (s, 3H).

Step 3

Example 356 was synthesized in the same manner as Example 18 usingExample 109 and 356-2. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H),7.76 (d, J=8.5 Hz, 1H), 7.23-7.15 (m, 2H), 7.12 (d, J=2.3 Hz, 1H), 6.99(s, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.11-5.99 (m, 1H), 5.61 (dd, J=15.2,8.9 Hz, 1H), 5.23 (t, J=3.7 Hz, 1H), 4.56-4.45 (m, 2H), 4.37 (dd,J=14.8, 6.4 Hz, 1H), 4.13-4.04 (m, 2H), 4.02-3.96 (m, 2H), 3.96-3.83 (m,4H), 3.78 (dd, J=8.9, 3.6 Hz, 1H), 3.73-3.66 (m, 4H), 3.28 (s, 3H), 3.09(dd, J=15.3, 10.2 Hz, 1H), 2.89-2.75 (m, 2H), 2.54-2.36 (m, 3H),2.29-2.09 (m, 4H), 1.97-1.71 (m, 6H), 1.50-1.40 (m, 1H), 1.16 (d, J=6.6Hz, 3H). LCMS-ESI+ (m/z): calcd H+ for C₄₁H₅₀ClN₅O₈S: 808.31; found:807.99.

Example 357

Example 357 was synthesized in the same manner as Example 75 using(1r,3r)-3-fluorocyclobutan-1-amine hydrochloride and Example 109. ¹H NMR(400 MHz, Methanol-d₄) δ 7.69 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H),7.09 (d, J=2.1 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.97 (s, 1H), 6.87 (d,J=8.2 Hz, 1H), 6.06 (d, J=15.4 Hz, 1H), 5.62 (dd, J=15.4, 8.9 Hz, 1H),4.41 (s, 1H), 4.23 (d, J=12.7 Hz, 1H), 4.03 (s, 2H), 3.89-3.71 (m, 3H),3.66 (d, J=14.2 Hz, 1H), 3.36 (s, 1H), 3.29 (s, 4H), 3.07 (dd, J=15.2,9.9 Hz, 1H), 2.89-2.70 (m, 3H), 2.64-2.50 (m, 3H), 2.50-2.31 (m, 5H),2.20 (s, 2H), 2.10 (d, J=13.6 Hz, 1H), 1.96 (s, 2H), 1.80 (d, J=6.9 Hz,2H), 1.41 (t, J=13.1 Hz, 1H), 1.14 (d, J=6.4 Hz, 3H). LCMS-ESI+[M+H]calc'd for C₃₇H₄₆ClFN₄O₅S: 713.29; found: 712.75.

Example 358

Example 358 was synthesized in the same manner as Example 18 using5-(methoxycarbonyl)-1-methyl-1H-pyrrole-3-carboxylic acid and Example109. ¹H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J=8.5 Hz, 1H), 7.51 (d,J=1.9 Hz, 1H), 7.41 (dd, J=6.4, 1.8 Hz, 1H), 7.20 (dd, J=8.5, 2.3 Hz,1H), 7.11 (d, J=2.4 Hz, 2H), 6.97 (d, J=8.2 Hz, 2H), 5.96 (dt, J=14.6,6.6 Hz, 1H), 5.59 (dd, J=15.5, 8.2 Hz, 1H), 4.17-4.03 (m, 2H), 4.00 (s,2H), 3.91-3.69 (m, 7H), 3.29 (d, J=5.6 Hz, 4H), 3.06-2.90 (m, 2H),2.88-2.68 (m, 3H), 2.45 (d, J=10.3 Hz, 2H), 2.32-1.57 (m, 8H), 1.48-1.23(m, 3H), 1.11 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₀H₄₇ClN₄O₇S: 763.29 found: 763.12.

Example 359

Method 1 Step 1

To a stirred solution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (500 mg, 1.068 mmol)in tetrahydrofuran was added pyridine (337 mg, 4.24 mmol) and aceticanhydride (545 mg, 5.34 mmol). The mixture was stirred at 60° C.overnight followed by evaporation of the solvents. The residue wasdissolved in ethyl acetate and washed with water. The organic layer wasconcentrated. Solids were dissolved in CH₂Cl₂ and cooled down to 0° C.To this mixture, SOCl₂ (2 mL) was added dropwise under vigorousstirring. The mixture was stirred at 0° C. and let it warm slowly toroom temperature. After reaction was completed, water was added to themixture and vigorously stirred overnight. Desired product was extractedin DCM. Organic phase was dried over Mg₂SO₄ and evaporated under reducedpressure to give intermediate 359-1.

Step 2

To a stirred solution of 359-1 (200 mg, 0.39 mmol) in DCM (10 mL) wasaddedN—((S)-amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-sulfanylidene)-2,2,2-trifluoroacetamide(110-2-2) (110 mg, 0.41 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (122 mg, 0.78 mmol)and 4-(dimethylamino)pyridine (96 mg, 0.78 mmol). The reaction mixturewas stirred at room temperature for 4 hr. Then the reaction mixture wasdiluted with DCM, washed with 1 N HCl, and brine. The organic phase wasdried over MgSO₄, filtered, concentrated down and purified by normalphase chromatography 20-80% EtOAc/hexanes to yield intermediate 359-2.

Step 3

Synthesis of Intermediate 359-3: To a stirred solution of intermediate359-2 (250 mg, 0.33 mmol), Hoveyda-Grubbs II (61 mg, 0.098 mmol) in1,2-dichloroethane (90 mL) was degassed with argon. The reaction mixturewas stirred at 60° C. overnight. The reaction mixture was concentratedand the residue was used on next step.

Step 4: Preparation of Intermediate 359-4

To a stirred solution of intermediate 359-3 (58 mg, 0.079 mmol) inmethanol (10 mL) was added water (1 mL) and K₂CO₃ (38 mg, 0.39 mmol) andstirred at 60° C. for 24 hrs. Water was added and the mixture extractedwith dichloromethane. The organic phase was dried over anhydrousmagnesium sulfate and the solvent removed under reduced pressure.

Step 5

Example 359 was synthesized in the same manner as Example 18 using3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid and intermediate 359-4.1H NMR (400 MHz, Chloroform-d) δ 7.83-7.66 (m, 3H), δ 7.33 (s, 1H), 7.21(dd, J=8.5, 2.3 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H),5.85-5.74 (m, 1H), 5.70-5.62 (m, 1H), 4.19-4.00 (m, 3H), 3.80 (s, 3H),3.31 (d, J=14.2 Hz, 2H), 3.07 (d, J=15.7 Hz, 2H), 2.89-2.69 (m, 3H),2.61-2.35 (m, 3H), 2.25-1.67 (m, 10H), 1.58 (d, J=7.2 Hz, 3H), 1.44 (t,J=12.5 Hz, 2H), 1.28 (s, 2H), 1.02 (d, J=6.7 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₃₈H₄₆ClN₅O₆S: 736.29; found: 736.10.

Method 2

Step 1

tert-Buty 1 chlorodimethylsilane (4.5 g, 1.2 equiv) was added to asolution of(S)-6′-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carboxylic acid (12 g, 24.9 mmol) andimidazole (2.2 g, 1.3 equiv) in DMF (60 mL). After 2 hr, the reactionwas diluted with EtOAc and washed with water, 5% aqueous LiCl and brine.The organic phase was dried over sodium sulfate and the solvent wasremoved under reduced pressure. The residue was subjected to flashcolumn chromatography (silica gel, 0-100% EtOAc/hexanes). The fractionscontaining product were combined and the solvent was removed underreduced pressure, providing 359-2-1 (14.5 g, 97%). ¹H NMR (400 MHz,Chloroform-d) δ 7.69 (d, J=8.5 Hz, 1H), 7.46-7.38 (m, 2H), 7.18 (dd,J=8.5, 2.4 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 6.97-6.90 (m, 1H), 5.82(ddd, J=16.7, 10.4, 6.0 Hz, 1H), 5.23 (dt, J=17.1, 1.6 Hz, 1H), 5.05(dt, J=10.5, 1.5 Hz, 1H), 4.20-4.03 (m, 4H), 3.90 (s, 3H), 3.59 (d,J=14.2 Hz, 1H), 3.48 (dd, J=14.5, 4.0 Hz, 1H), 3.38-3.21 (m, 2H), 2.79(q, J=5.3 Hz, 2H), 2.69 (td, J=8.7, 3.9 Hz, 1H), 2.22-2.10 (m, 1H),2.10-1.86 (m, 2H), 1.77-1.68 (m, 2H), 1.65-1.49 (m, J=9.3 Hz, 3H), 0.91(s, 9H), 0.05 (s, 3H), 0.05 (s, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₄H₄₆ClNO₄Si: 596.3; found: 596.2.

Step 2

Intermediate 359-2-1 (14.5 g, 24.3 mmol) was combined with lithiumhydroxide (2.3 g, 4 equiv), water (97 mL), methanol (100 mL) andtetrahydrofuran (150 mL). The mixture was heated at 60° C. for 5 hr. Thereaction was concentrated in vacuo, then the remaining solution wasacidified with 1 N aqueous HCl (120 mL). The mixture was extracted withEtOAc, and the combined organic phases were dried over sodium sulfateand concentrated under reduced pressure, providing intermediate 359-2-2.¹H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J=8.5 Hz, 1H), 7.52-7.46 (m,2H), 7.19 (dd, J=8.5, 2.4 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 6.96 (d,J=8.7 Hz, 1H), 5.80 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.24 (dt, J=17.2,1.6 Hz, 1H), 5.05 (dt, J=10.6, 1.5 Hz, 1H), 4.19-4.04 (m, 4H), 3.61 (d,J=14.3 Hz, 1H), 3.51 (dd, J=14.5, 4.0 Hz, 1H), 3.36 (d, J=14.3 Hz, 1H),3.28 (dd, J=14.5, 9.5 Hz, 1H), 2.79 (d, J=4.5 Hz, 2H), 2.71 (td, J=8.7,4.0 Hz, 1H), 2.20-2.11 (m, 1H), 2.06-1.83 (m, 1H), 1.77 (q, J=8.4, 7.8Hz, 2H), 1.65 (q, J=9.3 Hz, 2H), 1.55 (q, J=12.9, 12.2 Hz, 2H), 0.91 (s,9H), 0.05 (d, J=4.5 Hz, 6H). LCMS-ESI+ (m/z): [M+H]⁺ calcd forC₃₃H₄₄ClNO₄Si: 582.3; found: 582.5.

Step 3

Intermediate 359-2-2 (13.2 g, 22.7 mmol) was combined with Intermediate110-1-2 (7.72 g, 1.05 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.87 g, 1.10 equiv),4-dimethylaminopyridine, (3.05 g, 1.10 equiv), and DCM (160 mL) werecombined and stirred at room temperature for 2 hr. The reaction wasdiluted with DCM (200 mL) and washed with water (150 mL), saturatedNaHCO₃ (150 mL) and saturated NH₄Cl (150 mL). The organic phase wasdried over sodium sulfate and the solvent was removed under reducedpressure. The residue was subjected to flash column chromatography(silica gel, 0-100% EtOAc/hexanes). The fractions containing productwere combined and the solvent was removed under reduced pressure,providing intermediate 359-2-3. LCMS-ESI+ (m/z): [M+H]⁺ calcd forC₄₉H₆₆ClN₃O₆SSi: 888.4; found: 889.6.

Step 4

Intermediate 359-2-3 (16.2 g, 18.2 mmol) was combined with DCM (300 mL)and trifluoroacetic acid (100 mL) and stirred at room temperature for 16hr. The above reagents were combined and stirred at RT for 16 h. Themajority of the volatiles were removed under reduced pressure. Theresidue was diluted with DCM (100 mL). This solution was washed with satNaHCO₃ (2×300 mL). The aqueous was washed with DCM (50 mL). The combinedorganic phases were washed with brine and dried over sodium sulfate andthe solvent was removed under reduced pressure. The residue wassubjected to flash chromatography (0-100% EtOAc/hexanes). The fractionscontaining product were combined and the solvent was removed underreduced pressure providing intermediate 359-2-4. ¹H NMR (400 MHz,Chloroform-d) δ 7.83 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.51(dd, J=8.2, 1.9 Hz, 1H), 7.19 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d, J=2.3Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 5.85 (ddt, J=16.2, 11.4, 5.7 Hz, 1H),5.75 (dt, J=10.4, 7.3 Hz, 1H), 5.33-5.23 (m, 1H), 5.15-5.06 (m, 3H),4.21-4.03 (m, 1H), 3.94 (d, J=14.8 Hz, 1H), 3.66 (d, J=14.2 Hz, 1H),3.60-3.48 (m, 1H), 3.26 (d, J=14.2 Hz, 1H), 3.12 (dd, J=14.8, 8.9 Hz,1H), 2.81-2.71 (m, 3H), 2.58 (dt, J=18.8, 8.5 Hz, 2H), 2.18 (dd, J=13.9,6.6 Hz, 1H), 2.11-1.99 (m, 5H), 1.99-1.89 (m, 1H), 1.85 (q, J=9.2, 8.6Hz, 2H), 1.74-1.43 (m, 3H), 1.37 (d, J=7.0 Hz, 3H), 1.12 (d, J=6.8 Hz,3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₄H₄₄ClN₃O₄S: 626.3; found:626.8.

Step 5

A solution of intermediate 359-2-4 (300 mg, 0.48 mmol) in DCE (20 mL)was degassed with argon for 5 min. MgO (60 mg, 3.0 equiv) andHoveyda-Grubbs II catalyst (60 mg, 0.20 equiv) were added. The mixturewas stirred and degassed for 10 min. The mixture was heated at 70° C.for 2 hr. The reaction was cooled and ACN was added. The solvent wasremoved under reduced pressure. The residue was subjected to flashcolumn chromatography (silica gel, 20-100% (20% MeOH/EtOAc)/hexanes).The fractions containing product were combined and the solvent wasremoved under reduced pressure, providing intermediate 359-4. ¹H NMR(400 MHz, Chloroform-d) δ 7.77 (d, J=8.5 Hz, 1H), 7.50-7.43 (m, 2H),7.20 (dd, J=8.5, 2.3 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.1 Hz,1H), 6.42 (s, 2H), 5.81 (dd, J=16.1, 4.2 Hz, 1H), 5.77-5.65 (m, 1H),4.20 (s, 1H), 4.10 (d, J=6.5 Hz, 2H), 3.83 (dd, J=15.3, 5.8 Hz, 1H),3.77 (d, J=14.5 Hz, 1H), 3.57 (t, J=7.2 Hz, 1H), 3.37 (d, 1H), 3.15-3.07(m, 1H), 2.83-2.73 (m, 3H), 2.73-2.60 (m, 1H), 2.51 (dt, J=17.1, 9.6 Hz,2H), 2.16 (t, J=14.5 Hz, 1H), 2.08-2.02 (m, 1H), 2.01-1.77 (m, 4H),1.72-1.47 (dd, J=18.1, 9.2 Hz, 4H), 1.41 (m, 4H), 1.11 (d, J=6.9 Hz,3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₄₀ClN₃O₄S: 598.3; found:598.5.

Step 6

Example 359 was prepared in a manner similar to Example 18, usingintermediate 359-4 and 1-methyl-1H-pyrazole-4-carboxylic acid.

Example 360

Step 1: Preparation of trans-3-((tert-butoxycarbonyl)amino)cyclobutylDimethylcarbamate

tert-butyl trans-(3-hydroxycyclobutyl)carbamate (1000.0 mg, 5.341 mmol)was treated with dimethylcarbamic chloride (1723.0 mg, 16.02 mmol, 3.0equiv.) in the presence of DMAP (1957.5 mg, 16.02 mmol, 3 equiv.) andDIPEA (3451.4 mg, 26.70 mmol, 5 equiv.) in DCE (20 mL) at 60° C. for 15h. The reaction mixture was quenched with water (30 mL) and the wholewas extracted with EtOAc (30 mL×3). Obtained organic layer was washedwith brine (30 mL) and dried over Na₂SO₄. The solvent was removed undera reduced pressure. Obtained crude mixture was purified by a silica-gelcolumn chromatography (13-50% EtOAc/hexane) to givetrans-3-((tert-butoxycarbonyl)amino)cyclobutyl dimethylcarbamate.

Step 2: Preparation of trans-3-aminocyclobutyl dimethylcarbamatebis-hydrochloric Acid

trans-3-((tert-butoxycarbonyl)amino)cyclobutyl dimethylcarbamate (114.2mg, 0.442 mmol) was treated with 4 N—HCl (6 mL) at rt. After 2 h, thesolvent was removed under a reduced pressure to givetrans-3-aminocyclobutyl dimethylcarbamate bis-hydrochloric acid.

Step 3

Example 360 was synthesized in the same manner as Example 75 usingtrans-3-aminocyclobutyl dimethylcarbamate bis-hydrochloric acid andExample 109. ¹H NMR (400 MHz, Acetone-d₆) δ 7.70 (d, J=8.5 Hz, 1H), 7.56(s, 1H), 7.28 (s, 1H), 7.12 (dd, J=8.5, 2.3 Hz, 1H), 7.04 (d, J=2.2 Hz,1H), 6.77 (d, J=8.2 Hz, 1H), 6.10 (br s, 1H), 5.48 (br s, 1H), 4.96(brs, 1H), 4.30 (br s, 1H), 4.00 (s, 2H), 3.94-3.55 (m, 3H), 3.51-3.16(m, 7H), 2.89 (d, J=13.0 Hz, 6H), 2.75 (d, J=16.5 Hz, 2H), 2.64-1.55 (m,16H), 1.38 (t, J=12.6 Hz, 1H), 1.02 (d, J=6.7 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₄₀H₅₃ClN₅O₇S: 782.33; found: 781.74.

Example 361

Example 361 was synthesized in the same manner as Example 75 using3-methoxybicyclo[1.1.1]pentan-1-amine hydrochloric acid and Example 109.¹H NMR (400 MHz, Methanol-d₄) 7.69 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 7.25(br s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.07-6.96 (m, 2H), 6.80 (d, J=8.2Hz, 1H), 6.08 (m, 1H), 5.50 (m, 1H), 4.05-3.92 (m, 3H), 3.89-3.62 (m,3H), 3.42 (d, J=10.2 Hz, 1H), 3.29 (s, 3H), 3.25 (s, 3H), 3.13 (dd,J=15.2, 10.2 Hz, 1H), 2.79-2.06 (m, 11H), 1.99 (s, 6H), 1.97-1.67 (m,3H), 1.48-1.33 (m, 1H), 1.05 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+calcd for C₃₉H₅₀ClN₄O₆S: 737.31; found: 736.72.

Example 362

A 4-dram vial was charged with Example 109 (1 equiv, 0.025 mmol, 15 mg),diphenyl carbonate (8 equiv, 0.201 mmol, 43.0 mg),N,N-dimethylaminopyridine (5 equiv, 0.125 mmol, 15.3 mg) and MeCN (0.75mL). The reaction vial was sealed and stirred at room temperatureovernight. In a separate vial, 3-methoxyazetidine hydrochloride (10equiv, 0.251 mmol, 31.0 mg) was treated with MeCN (0.5 mL) andtriethylamine (40 equiv, 1.0 mmol, 0.14 mL) then combined with thereaction mixture, sealed and heated to 50° C. for 3 hours. The reactionmixture was concentrated and purified by preparative HPLC (60-100% MeCNin water, 0.1% TFA) and lyophilized to afford the desired productExample 362. LCMS-ESI+ (m/z): [M+H]⁺ calc'd for C₃₇H₄₇ClN₄O₆S: 711.2978;found: 710.79. ¹H NMR (400 MHz, Methanol-d₄) δ 7.73 (d, J=8.5 Hz, 1H),7.17 (dd, J=8.5, 2.4 Hz, 1H), 7.14-7.02 (m, 2H), 6.96-6.85 (m, 2H), 5.96(dt, J=14.2, 6.7 Hz, 1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 4.29 (dd,J=14.9, 6.3 Hz, 1H), 4.20 (s, 3H), 4.06 (d, J=2.2 Hz, 2H), 3.83 (d,J=15.2 Hz, 3H), 3.74 (dd, J=9.2, 3.7 Hz, 1H), 3.63 (t, J=17.6 Hz, 2H),3.30 (s, 3H), 3.30-3.25 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J=15.2, 10.3Hz, 1H), 2.87-2.66 (m, 2H), 2.45 (dd, J=12.6, 7.9 Hz, 2H), 2.32 (p,J=9.1 Hz, 1H), 2.14 (ddd, J=27.8, 14.4, 8.6 Hz, 3H), 2.01-1.63 (m, 6H),1.42 (dd, J=14.2, 10.8 Hz, 1H), 1.13 (d, J=6.6 Hz, 3H).

Example 363

Example 363 was synthesized in the same manner as Example 362, usingExample 109 and 3-methoxy-3-methyl-azetidine hydrochloride. LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₃₈H₄₉ClN₄O₆S: 725.3134; found: 724.90. ¹H NMR(400 MHz, Methanol-d₄) δ 7.73 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5, 2.3Hz, 1H), 7.13-7.05 (m, 2H), 6.95-6.86 (m, 2H), 5.96 (dt, J=14.2, 6.7 Hz,1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 4.29 (dd, J=14.9, 6.3 Hz, 1H),4.11-4.02 (m, 2H), 3.97 (s, 2H), 3.88-3.54 (m, 6H), 3.31-3.29 (m, 1H),3.26 (s, 3H), 3.24 (s, 3H), 3.06 (dd, J=15.3, 10.3 Hz, 1H), 2.87-2.69(m, 2H), 2.52-2.40 (m, 2H), 2.33 (q, J=9.0 Hz, 1H), 2.23-2.03 (m, 3H),1.98-1.66 (m, 6H), 1.48 (s, 3H), 1.45-1.36 (m, 1H), 1.13 (d, J=6.6 Hz,3H).

Example 364

An oven-dried 4-dram vial was charged with (1S,2R)-2-fluorocyclopropanecarboxylic acid (15 equiv, 0.376 mmol, 39.2 mg), toluene (0.75mL), triethylamine (16.5 equiv, 0.414 mmol, 0.058 mL) anddiphenylphosphoryl azide (15 equiv, 0.376 mmol, 0.081 mL). The vial wassealed and heated to 85° C. in a pre-heated sand bath for 2 hours. Thereaction mixture was then cooled to room temperature, treated withExample 109 (1 equiv, 0.025 mmol, 15 mg), sealed and heated to 45° C.for 3 hours. The reaction mixture was cooled to room temperature,diluted with EtOAc, washed with half-saturated aqueous NaHCO₃,neutralized with 1 N HCl, and washed with brine. The organic layer wasdried over sodium sulfate, filtered and concentrated. The crude reactionmixture was purified by preparative HPLC (60-100% MeCN in water, 0.1%TFA) and lyophilized to afford the desired product Example 364.LCMS-ESI+(m/z): [M+H]⁺ calc'd for C₃₆H₄₄ClFN₄O₅S: 699.2778; found:698.72. ¹H NMR (400 MHz, Methanol-<74) δ 7.71 (d, J=8.5 Hz, 1H),7.19-7.05 (m, 3H), 6.98-6.84 (m, 2H), 5.99 (dd, J=14.6, 7.5 Hz, 1H),5.58 (dd, J=15.2, 9.0 Hz, 1H), 4.69-4.46 (m, 1H), 4.26 (dd, J=14.9, 6.4Hz, 1H), 4.11-3.98 (m, 2H), 3.86-3.61 (m, 4H), 3.30-3.26 (m, 1H), 3.25(s, 3H), 3.05 (dd, J=15.2, 10.3 Hz, 1H), 2.95 (ddd, J=20.9, 10.0, 5.1Hz, 1H), 2.87-2.68 (m, 2H), 2.55-2.41 (m, 2H), 2.41-2.29 (m, 1H),2.25-2.04 (m, 3H), 2.01-1.67 (m, 6H), 1.41 (t, J=12.2 Hz, 1H), 1.37-1.22(m, 1H), 1.12 (d, J=6.4 Hz, 3H), 0.96 (dddd, J=11.9, 7.8, 6.7, 5.3 Hz,1H).

Example 365

Example 365 was synthesized in the same manner as Example 316, usingintermediate 316-3 (directly in Step 3) and Example 109. The absoluteconfiguration of the cis cyclopropane stereocenters has not beendetermined and is denoted arbitrarily. LCMS-ESI+(m/z): [M+H]⁺ calc'd forC₃₇H₄₇ClN₄O₆S: 711.2978; found: 710.84. ¹H NMR (400 MHz, Methanol-d₄) δ7.73 (d, J=8.5 Hz, 1H), 7.19-7.12 (m, 2H), 7.10 (d, J=2.2 Hz, 1H), 6.95(s, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.01 (dt, J=14.3, 6.8 Hz, 1H), 5.57(dd, J=15.3, 8.9 Hz, 1H), 4.26 (td, J=15.5, 6.5 Hz, 1H), 4.11-3.98 (m,2H), 3.89-3.60 (m, 5H), 3.44-3.36 (m, 1H), 3.31-3.26 (m, 1H), 3.25 (s,3H), 3.05 (dd, J=15.2, 10.4 Hz, 1H), 2.87-2.63 (m, 3H), 2.54-2.41 (m,2H), 2.35 (dt, J=17.7, 9.6 Hz, 1H), 2.25-2.03 (m, 3H), 2.01-1.66 (m,6H), 1.42 (t, J=13.8 Hz, 1H), 1.35-1.21 (m, 1H), 1.12 (d, J=6.3 Hz, 3H),0.99 (q, J=7.4 Hz, 1H), 0.44 (q, J=5.6 Hz, 1H).

Example 366

Example 366 was synthesized in the same manner as Example 367 usingExample 223 and 4-(2-iodoethyl)morpholine instead of iodoethane.LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₃H₅₅ClN₆O₇S: 835.4; found: 835.0.

Example 367

Example 223 (10 mg, 0.014 mmol) was dissolved in DMF (0.1 mL). NaH wasadded at room temperature followed by iodoethane (10 equiv.). Thereaction mixture was heated to 80° C. via a metal heating block. Theprogress of the reaction was monitored by LCMS. Upon observing the fullconsumption of the starting material, the residue was directly purifiedGilson reverse phase HPLC (60:40→100 MeCN/H₂O, 0.1% TFA) to affordExample 367. LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₈ClN₅O₆S: 750.3;found: 750.0.

Example 368

Step 1

To a stirred solution of (S)-6′-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene]-7-carbonylchloride (600 mg, 1.19 mmol) in acetonitrile (12 mL) was addedpyridazine (105 mg, 1.31 mmol) at room temperature and stirred for 10min. A solution of a mixture of diastereomers(3R)—N′-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonimidamide (383 mg,1.31 mmol) in acetonitrile was added and stirred at room temperatureovernight. Then the reaction mixture was diluted with DCM, washed withwater and brine. The organic phase was dried over MgSO₄, filtered, andconcentrated down to yield 368-1.

Step 2

To a stirred solution of 368-1 (700 g, 1.09 mmol) in DCM (14 mL) wasadded di-tert-butyl dicarbonate (334 mg, 1.53 mmol), trimethylamine (132mg, 1.3 mmol) and 4-(dimethylamino)pyridine (13 mg, 0.10 mmol). Thereaction mixture was stirred at room temperature for 1 hr. Then thereaction mixture was diluted with DCM, washed with 1N HCl, brine, andthen a saturated aqueous solution of NaHCO₃. The organic phase was driedover MgSO₄, filtered, and concentrated to yield 368-2.

Step 3

To a stirred solution of 368-2 (600 mg, 0.81 mmol) and Hoveyda-Grubbs II(50.6 mg, 0.08 mmol) in 1,2-dichloroethane (270 mL) was degassed withargon. The reaction mixture was stirred at 60° C. overnight. Thereaction mixture was concentrated and purified on reversed phasechromatography 0.1% TFA 65-95% acetonitrile to give 368-3.

Step 4

To a stirred solution of 368-3 (80 mg, 0.13 mmol) in DCM (5 mL) wasadded 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid (31 mg, 0.196 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (40 mg, 0.26 mmol),and 4-(dimethylamino)pyridine (31.9 mg, 0.26 mmol). The reaction mixturewas stirred at room temperature for 24 hr. Then the reaction mixture wasdiluted with DCM, and washed with 1N HCl and brine. The organic phasewas dried over MgSO₄, filtered, concentrated, and purified on reversedphase chromatography 0.1% TFA 70-95% acetonitrile to give Example 368.1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J=8.5 Hz, 1H), 7.45 (dd,J=8.3, 1.9 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.16 (dd, J=8.5, 2.3 Hz,1H), 7.07 (d, J=2.3 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 5.75 (td, J=11.0,5.2 Hz, 1H), 5.38 (t, J=10.3 Hz, 1H), 4.16 (s, 3H), 4.11-3.92 (m, 5H),3.84 (d, J=15.3 Hz, 1H), 3.78-3.67 (m, 2H), 3.55 (ddd, J=11.8, 8.7, 4.1Hz, 3H), 3.41 (d, J=14.7 Hz, 2H), 3.31 (s, 5H), 2.96-2.64 (m, 3H), 2.39(q, J=8.8 Hz, 1H), 2.28 (t, J=13.7 Hz, 2H), 2.19-1.58 (m, 15H), 1.42 (t,J=12.8 Hz, 1H), 1.25 (s, 2H), 1.02 (t, J=7.4 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₄₀H₅₂ClN₃O₇S: 754.32; found: 754.15.

Example 369

Example 369 Step 1

(3R,4S)-3-Fluorotetrahydro-2H-pyran-4-ol (500 mg, 4.162 mmol) and benzyl2-bromoacetate (1.049 g, 4.579 mmol, 1.1 equiv) were treated with KHMDS(1.0 M in THF, 4.16 mL, 4.16 mmol) in THF (15 mL) at −78° C. for 2 h.The resulting mixture was concentrated by removing THF and the residuewas suspended into CH₂Cl₂. The suspension was filtered and the filtratewas concentrated to give a crude product. The crude product was purifiedby a silica-gel column chromatography (0-40% EtOAc/hexane) to givebenzyl 2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)acetate. 1H NMR(400 MHz, Methanol-d4) δ 7.41-7.29 (m, 5H), 5.21 (s, 2H), 4.30 (s, 2H),4.03-3.96 (m, 1H), 3.92-3.87 (m, 1H), 3.81-3.70 (m, 1H), 3.61-3.41 (m,3H), 2.02-1.92 (m, 1H), 1.86-1.80 (m, 1H).

Step 2

Benzyl 2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)acetate (50.0mg, 1.983 mg) was treated with 10% Pd/C (1.9 mg) in EtOAc (5 mL) underatmospheric pressure of a hydrogen atmosphere for 2 h. The catalyst wasfiltered off through Celite and obtained filtrate was concentrated.Crude 2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)acetic acid wasimmediately used for the subsequent step without further purificationand characterizations.

Step 3

Example 369 was synthesized in the same manner as Example 21 using2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)acetic acid. 1H NMR(400 MHz, Chloroform-d) δ 7.74 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.2, 1.8Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J=8.5, 2.3 Hz, 1H), 7.07 (d, J=2.3 Hz,1H), 6.91 (d, J=8.2 Hz, 1H), 5.93-5.64 (m, 2H), 4.98-4.77 (m, 1H),4.35-4.20 (m, 2H), 4.15-3.97 (m, 4H), 3.88 (p, J=9.4 Hz, 3H), 3.81-3.51(m, 5H), 3.29 (s, 3H), 3.06-2.96 (m, 1H), 2.81-2.69 (m, 3H), 2.47-2.21(m, 4H), 2.14-2.02 (m, 4H), 1.92 (p, J=8.6 Hz, 3H), 1.77-1.69 (m, 3H),1.38 (t, J=12.9 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₃₈H₄₇ClFN₃O₇S: 744.28; found: 744.28.

Example 370

¹H NMR (400 MHz, Methanol-d₄) δ 7.75 (d, J=8.4 Hz, 1H), 7.19 (dd, J=8.4,2.4 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8.2, 1.8 Hz, 1H),6.95-6.93 (m, 2H), 5.99-5.92 (m, 1H), 5.59 (dd, J=15.2, 9.2 Hz, 1H),4.54-4.49 (m, 1H), 4.13-4.07 (m, 2H), 3.84 (d, J=15.2 Hz, 1H), 3.73 (dd,J=9.4, 3.4 Hz, 1H), 3.65 (d, J=14.0 Hz, 1H), 3.37-3.29 (m, 2H), 3.24 (s,3H), 3.16-3.06 (m, 1H), 2.88-2.73 (m, 3H), 2.50-1.72 (m, 10H), 1.57 (d,J=7.2 Hz, 3H), 1.45 (t, J=13.0 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H). LCMS-ESC(m/z): [M+H]⁺ calculated for C₃₅H₄₁ClF₃N₃O₅S: 708.25; found: 708.2.

Example 371

The mixture of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid (2.6 mg,0.0196 mmol) and Example 110 (8.0 mg, 0.0131 mmol) in DCM (1.0 mL) wascooled to 0° C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCl salt(5.0 mg, 0.0261 mmol) was added followed by DMAP (3.2 mg, 0.0261 mmol).The reaction was removed from the cooling bath and stirred at roomtemperature for overnight. The reaction was concentrated to remove DCM,diluted with DMF (1 mL), filtered and purified by Gilson reverse phaseprep HPLC (60-100% ACN/H₂O with 0.1% TFA). Desired fractions were pooledand frozen dried to give Example 371. LCMS-ESI+ (m/z): calcd H+ forC₃₉H₅₀ClN₃O₆S: 724.31; found: 723.99.

Example 372

Example 306 was synthesized in the same manner as Example 18 using7-hydroxy-5,6,7,8-tetrahydroindolizine-2-carboxylic acid and Example109. LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₁H₄₉ClN₄O₆S: 761.3; found:761.0.

Example 373

Step 1: Synthesis of 373-1

tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (139 mg, 0.742 mmol)was dissolved in DCM (5.0 mL) and cooled to 0° C., Dess-MartinPeriodinane (409 mg, 0.965 mmol) was added. The reaction was removedfrom the cooling bath and stirred at room temperature for 1 hr. Thereaction was then treated with 1N sodium thiosulfate (10.0 mL) and sat.NaHCO₃ (10.0 mL), stirred vigorously for 15 min. The mixture was thendiluted with DCM (20.0 mL), the layers were separated, and the organiclayer was washed with brine, dried over sodium sulfate, filtered, andconcentrated to give 373-1.

Step 2: Synthesis of 373-2

(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine;dihydrochloride (713 mg, 3.31 mmol) was suspended in DCM (10.0 mL) atroom temperature, 25 wt % NaOMe in MeOH (1.55 mL) was added dropwise.The resulting milky suspension was stirred at rt for 2 hrs. The reactionwas concentrated, treated with EtOAc at rt for 1 hr, then filtered. Thefiltrate was concentrated, and dried over the vacuum line for overnight.The free based material (57.6 mg, 0.405 mmol) was dissolved in DCM (4.0mL) at room temperature. 373-1 (50.0 mg, 0.27 mmol) was added. Themixture was stirred for 2 hrs before STAB (85.8 mg, 0.405 mmol) wasadded. The newly formed mixture was stirred for 1 h. The reaction wasconcentrated by removing DCM, redissolved in EtOAc, and treated with 1NNaOH, layers were separated. The aqueous layer was extracted with EtOActwice. Combined organic layer was dried over sodium sulfate, filtered,and concentrated to give 373-2. LCMS-ESI+ (m/z): calcd H+ forC₁₆H₂₉N₃O₃: 312.22; found: 312.23.

Step 3: Synthesis of 373-3

373-2 (84.0 mg, 0.27 mmol) was dissolved in DCM (1.0 mL) at roomtemperature, 4 N HCl in 1,4-dioxane (0.27 mL, 1.08 mmol) was added. Thereaction was stirred at room temperature for 1 hr. The reaction wasconcentrated, coevaporated with EtOAc three times, further dried overthe vacuum line to give 373-3.

Step 4

Example 373 was synthesized in the same manner as Example 75 usingExample 109 and 373-3 and DIEA. LCMS-ESI+ (m/z): calcd H+ forC₄₄H₅₉ClN₆O₆S: 835.39; found: 835.26.

Example 374

Example 374 was synthesized in the same manner as Example 279 usingExample 188 and selenium dioxide (40 eq). 1H NMR (400 MHz, Methanol-d4)δ 7.97 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.25-7.16 (m, 2H), 7.12 (d,J=2.3 Hz, 2H), 6.92 (dd, J=8.2, 2.1 Hz, 1H), 6.18-6.06 (m, 1H),5.82-5.74 (m, 1H), 4.43-4.26 (m, 2H), 4.10 (s, 2H), 3.99 (s, 3H),3.86-3.76 (m, 6H), 3.70-3.61 (m, 1H), 3.27 (s, 3H), 3.18-3.08 (m, 1H),2.91-2.72 (m, 2H), 2.57-2.27 (m, 3H), 2.14-2.05 (m, 1H), 1.99-1.79 (m,6H), 1.71 (d, J=7.0 Hz, 3H), 1.53-1.41 (m, 1H), 1.27 (d, J=8.8, 7.0 Hz,3H). LCMS-ESI+ (m/z): calcd H+ for C₃₉H₄₈ClN₅O₇S: 766.30; found: 765.05.

Example 375

Step 1

Example 109 (445 mg, 0.744 mmol) was dissolved in dioxane (7 mL).Selenium dioxide (330 mg, 4 equiv.) was added in one portion. Themixture was heated to reflux until LCMS indicated approximately 50%conversion to the corresponding allylic alcohol. The reaction mixturewas then cooled to room temperature and the residue was purified byGilson reverse phase prep HPLC (40-90% ACN/H₂O with 0.1% TFA) to giveintermediate 375-1. ¹H NMR (400 MHz, Methanol-d₄) δ 7.76 (d, J=8.6 Hz,1H), 7.29 (dd, J=8.2, 1.9 Hz, 1H), 7.18 (dd, J=8.6, 2.3 Hz, 1H), 7.11(d, J=2.4 Hz, 1H), 7.07 (d, J=1.9 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.25(dd, J=15.3, 6.1 Hz, 1H), 5.76 (dd, J=15.5, 9.0 Hz, 1H), 4.38 (d, J=6.0Hz, 1H), 4.26 (dd, J=15.0, 6.1 Hz, 1H), 4.09-4.00 (m, 2H), 3.93-3.81 (m,2H), 3.65 (d, J=14.1 Hz, 1H), 3.30 (m, 6H), 3.10-3.03 (m, 1H), 2.87-2.70(m, 3H), 2.57-2.30 (m, 2H), 2.25-2.09 (m, 2H), 2.01-1.66 (m, 7H), 1.43(t, J=12.7 Hz, 1H), 1.21 (d, J=6.9 Hz, 3H). LCMS-ESI+(m/z): [M+H]+ calcdfor C₃₂H₄₀ClN₃O₅S: 614.3; found: 614.1.

Step 2

Di-tert-butyl dicarbonate (16.9 mg, 77.4 μmol) was added to a stirredmixture of Intermediate 375-1 (31.7 mg, 51.6 μmol), triethylamine (21.6μL, 155 μmol), 4-(dimethylamino)pyridine (18.9 mg, 155 μmol), and water(4.6 μL, 260 μmol) in tetrahydrofuran (3.0 mL) at 0° C., and theresulting mixture was warmed to room temperature. After 40 min, asolution of citric acid (200 mg) in water (5 mL) was added. Ethylacetate (60 mL) was added. The organic layer was washed sequentiallywith water (30 mL) and a mixture of water and brine (1:1 v:v, 30 mL),then dried over anhydrous magnesium sulfate, filtered, and concentratedunder reduced pressure. The residue was dissolved in tetrahydrofuran(1.0 mL), stirred, and cooled to −40° C. Iodomethane (32.2 μL, 516 μmol)was added via syringe. After 1 min, potassium bis(trimethylsilyl)amidesolution (1.0 M in tetrahydrofuran) was added over 1 min via syringe.After 1 min, the resulting mixture was warmed to room temperature. After30 min, a solution of phosphoric acid (260 mg) and sodium dihydrogenphosphate dehydrate (90 mg) in water (10 mL) was added. Ethyl acetate(60 mL) was added. The organic layer was washed sequentially with amixture of water and brine (1:1 v:v, 30 mL) and brine (2×30 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was dissolved in dichloromethane (10 mL),and the resulting mixture was stirred at room temperature.Trifluoroacetic acid (1.0 mL) was added. After 20 min, trifluoroaceticacid (0.55 mL) was added. After 30 min, a solution of sodium dihydrogenphosphate dehydrate (6.3 g) in water (15 mL) was added. Brine (10 mL)was added, and the aqueous layer was extracted with dichloromethane(2×30 mL). The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel (0to 70% ethyl acetate in dichloromethane) to give 375-2.

Step 2

Example 375 was synthesized in a manner similar to Example 244 using375-2 instead of 240-1. 1H NMR (400 MHz, Acetone-d6) δ 7.77 (d, J=8.4Hz, 1H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.18-7.03 (m, 3H), 6.96 (d, J=8.1Hz, 1H), 5.94 (dd, J=15.3, 8.1 Hz, 1H), 5.80 (dd, J=15.3, 9.0 Hz, 1H),4.35-4.16 (m, 4H), 4.13 (d, J=12.2 Hz, 1H), 4.08 (d, J=12.1 Hz, 1H),3.97-3.44 (m, 6H), 3.39 (d, J=14.2 Hz, 1H), 3.30 (s, 3H), 3.28 (s, 3H),3.25 (s, 3H), 3.18 (dd, J=15.3, 10.4 Hz, 1H), 3.05-1.38 (m, 14H), 1.23(d, J=6.8 Hz, 3H). LCMS: 741.2.

Example 376

Example 376 was synthesized in the same manner as Example 283 using1-iodo-2-(2-methoxyethoxy)ethane and Example 279. ¹H NMR (400 MHz,Methanol-d₄) δ 8.09 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.41-7.31 (m, 1H),7.23-7.14 (m, 2H), 7.12 (m, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.05 (dd,J=15.4, 7.3 Hz, 1H), 5.85 (dd, J=15.4, 8.5 Hz, 1H), 4.15-4.01 (m, 9H),3.82 (m, 5H), 3.76-3.58 (m, 6H), 3.54-3.44 (m, 4H), 3.41 (d, J=14.4 Hz,1H), 3.35 (s, 3H), 3.30 (s, 3H), 3.19-3.06 (m, 1H), 2.89-2.73 (m, 2H),2.51 (br, 2H), 2.27 (m, 1H), 2.11 (m, 1H), 2.0-1.89 (m, 2H), 1.82 (m,3H), 1.46 (t, J=11.7 Hz, 1H), 1.20 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₄₃H₅₆ClN₅O₉S: 854.3; found: 854.1.

Example 377 and Example 378

2-(2-Tosylhydrazono)acetyl chloride (34.4 mg, 132 μmol) andN,N-dimethylaniline (33.5 μL, 264 μmol) were added sequentially to astirred solution of Example 279 (33.1 mg, 44.0 μmol) in dichloromethane(0.9 mL) at 0° C. After 7 min, the resulting mixture was warmed to roomtemperature. After 55 min, 2-(2-tosylhydrazono)acetyl chloride (80.0 mg,307 μmol) and ACV-dimethylaniline (80.0 μL, 630 μmol) were addedsequentially. After 13 min, the resulting mixture was cooled to 0° C.,and triethylamine (163 μL, 1.17 mmol) was added via syringe. After 20min, toluene (60 mL) and a mixture of sodium dihydrogen phosphatemonohydrate (160 mg) and sodium hydrogen phosphate heptahydrate (1.04 g)in water (100 mL) were added sequentially. The biphasic mixture wasagitated, and the layers were separated. The organic layer was washedsequentially with a mixture of sodium dihydrogen phosphate monohydrate(80 mg) and sodium hydrogen phosphate heptahydrate (502 mg) in water (50mL), a solution of citric acid (100 mg) in water (50 mL), and water (50mL); dried over anhydrous sodium sulfate; filtered; and concentratedunder reduced pressure to a volume of 8.5 mL. The resulting mixturecontaining crude 377-1 was added over 90 min via syringe pump to avigorously stirred mixture of copper(I) trifluoromethanesulfonatetoluene complex (6.7 mg, 22 μmol) and toluene (5.0 mL) at 100° C. After15 min, the resulting mixture was cooled to room temperature, wasfiltered through celite, and was concentrated under reduced pressure.The residue was purified by reverse phase preparative hplc (0.1%trifluoroacetic acid in acetonitrile/water) to give Example 377 as a 1:1mixture of diastereomers. 1H NMR (400 MHz, Acetone-d6) δ 8.21-6.64 (m,11H), 6.20-5.79 (m, 1H), 5.74-5.14 (m, 2H), 4.25-2.99 (m, 17H),2.99-1.17 (m, 17H), 1.13 (d, J=6.9 Hz, 1.5H), 1.06 (d, J=6.9 Hz, 1.5H).LCMS: 890.1. Further elution gave Example 378. 1H NMR (400 MHz,Acetone-d6) δ 8.10 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.53-6.32 (m, 10H),6.32-5.21 (m, 3H), 4.29-2.84 (m, 8H), 4.08 (s, 3H), 3.85 (s, 3H), 3.23(s, 3H), 2.83-1.21 (m, 18H), 1.15 (d, J=6.8 Hz, 3H). LCMS: 884.2.

Example 379 Step 1: Preparation of Ethyl3-(3-methoxyazetidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylate

The reaction mixture of ethyl 3-bromo-1-methyl-pyrazole-4-carboxylate(150 mg, 0.64 mmol), 3-methoxyazetidine hydrochloride (119.3 mg, 0.97mmol), Cs₂CO₃ (629.09 mg, 1.93 mmol) and XanTphos Pd G3 (122.07 mg, 0.13mmol) in N-Methyl-2-pyrrolidone (3 mL) was heated at 120° C. overnight.The reaction mixture was cooled down, washed with water, extracted withEtOAc, dried over MgSO₄, filtered, concentrated, and purified by silicagel column (eluting with 0-100% EtOAc/hexane) to give the product.

Step 2: Preparation of3-(3-methoxyazetidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic Acid

the reaction mixture of ethyl3-(3-methoxyazetidin-1-yl)-1-methyl-pyrazole-4-carboxylate (14 mg, 0.06mmol), 2M NaOH (0.06 mL) in EtOH (1.0 mL) and water (0.5 mL) was stirredat 45° C. overnight. The reaction mixture was cooled down, concentrated,co-evaporated with toluene to remove moisture and go to the next stepwithout purification.

Step 3

Example 379 was synthesized in the same manner as Example 18, usingExample 109 instead of Example 5, and3-(3-methoxyazetidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid wasused instead of 3-methoxypropionic acid. 1H NMR (400 MHz, Methanol-d4) δ7.82-7.70 (m, 2H), 7.29 (d, J=8.3 Hz, 1H), 7.19 (dd, J=8.6, 2.3 Hz, 1H),7.14-7.04 (m, 2H), 6.91 (d, J=8.2 Hz, 1H), 6.10 (dt, J=14.2, 6.7 Hz,1H), 5.61 (dd, J=15.4, 8.6 Hz, 1H), 4.56 (dd, J=8.8, 6.3 Hz, 1H),4.51-4.45 (m, 1H), 4.33-4.23 (m, 2H), 4.19 (dd, J=8.7, 4.4 Hz, 1H),4.13-4.02 (m, 3H), 4.02-3.91 (m, 2H), 3.86 (d, J=15.1 Hz, 1H), 3.78 (dd,J=8.5, 2.8 Hz, 1H), 3.74 (s, 2H), 3.69 (d, J=14.3 Hz, 1H), 3.29 (s, 3H),3.08 (dd, J=14.9, 9.3 Hz, 2H), 2.92-2.70 (m, 3H), 2.49 (d, J=26.9 Hz,4H), 2.33-2.19 (m, 2H), 2.19-2.05 (m, 2H), 2.02-1.73 (m, 6H), 1.46 (d,J=11.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₄₁H₅₁ClN₆O₆S: 791.33; found: 791.13.

Example 380 Step 1: Preparation of Ethyl3-(4-methoxy-1-piperidyl)-1-methyl-pyrazole-4-carboxylate

The reaction mixture of ethyl 3-bromo-1-methyl-pyrazole-4-carboxylate(200 mg, 0.86 mmol), 4-methoxypiperidine (197.67 mg, 1.72 mmol), Cs₂CO₃(838.79 mg, 2.57 mmol) and XanTphos Pd G3 (162.76 mg, 0.17 mmol) indimethylacetamide (5 mL) was heated at 120° C. overnight. The reactionmixture was cooled down, washed with water, extracted with EtOAc, driedover MgSO₄, filtered, concentrated, and purified by silica gelchromatography (0-100% EtOAc/hexane) to give the product (14 mg).

Step 2: Preparation of3-(4-methoxy-1-piperidyl)-1-methyl-pyrazole-4-carboxylic Acid

The reaction mixture of ethyl3-(4-methoxy-1-piperidyl)-1-methyl-pyrazole-4-carboxylate (14 mg, 0.05mmol), 2M NaOH (0.05 ml) in EtOH (1 mL) and water (0.5 mL) was heated at45° C. overnight. The reaction mixture was then cooled down,concentrated, co-evaporated with toluene to remove moisture and go tonext step without purification.

Step 3

Example 380 was synthesized in the same manner as Example 18, usingExample 109 instead of Example 5, and3-(4-methoxy-1-piperidyl)-1-methyl-pyrazole-4-carboxylic acid was usedinstead of 3-methoxypropionic acid. 1H NMR (400 MHz, Methanol-d4) δ 7.92(s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.2, 1.9 Hz, 1H), 7.19 (dd,J=8.5, 2.3 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.07 (s, 1H), 6.91 (d, J=8.2Hz, 1H), 6.11 (dt, J=14.5, 6.9 Hz, 1H), 5.62 (dd, J=15.3, 8.7 Hz, 1H),4.32 (dd, J=14.8, 6.4 Hz, 1H), 4.14-3.97 (m, 3H), 3.91-3.74 (m, 5H),3.70 (d, J=14.3 Hz, 1H), 3.52-3.45 (m, 1H), 3.42 (s, 2H), 3.29 (s, 3H),3.27-3.22 (m, 3H), 3.13-3.00 (m, 2H), 2.90-2.69 (m, 3H), 2.46 (s, 3H),2.36-2.20 (m, 2H), 2.10 (t, J=17.1 Hz, 4H), 1.94 (d, J=5.1 Hz, 2H),1.91-1.65 (m, 6H), 1.45 (t, J=11.8 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₃H₅₅ClN₆O₆S: 819.36; found: 819.20.

Example 381

Example 381 was synthesized in the same manner as Example 223 using3-methylbutanoic acid and intermediate 266-2. 1H NMR (400 MHz,Chloroform-d) δ 7.84 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.3,1.9 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.5, 2.3 Hz, 1H), 7.10(d, J=2.3 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 5.93 (dt, J=13.6, 6.6 Hz,1H), 5.73 (dd, J=15.7, 6.1 Hz, 1H), 5.33 (t, J=5.7 Hz, 1H), 4.21-3.97(m, 6H), 3.96-3.62 (m, 6H), 3.32 (d, J=14.4 Hz, 1H), 3.04 (dd, J=15.2,9.6 Hz, 1H), 2.88-2.70 (m, 2H), 2.61 (d, J=18.4 Hz, 1H), 2.55-2.23 (m,3H), 2.20-1.99 (m, 4H), 1.97-1.60 (m, 5H), 1.34 (d, J=52.1 Hz, 3H), 1.12(d, J=6.8 Hz, 3H), 0.94 (dd, J=6.4, 5.2 Hz, 6H). LCMS-ESI+ (m/z): [M+H]+calcd for C₄₂H₅₂ClN₅O₇S: 807.42; found: 807.17.

Example 382

Example 382 was synthesized in the same manner as Example 75 usingExample 109 and tert-butyl (2R)-2-methylpiperazine-1-carboxylate. 1H NMR(400 MHz, Methanol-d4) δ 7.74 (d, J=8.6 Hz, 1H), 7.18 (dd, J=8.5, 2.4Hz, 1H), 7.14-7.07 (m, 2H), 6.95 (dd, J=8.1, 1.7 Hz, 1H), 6.88 (d, J=2.0Hz, 1H), 6.01-5.90 (m, 1H), 5.58 (dd, J=15.2, 9.3 Hz, 1H), 4.40 (dd,J=14.8, 6.3 Hz, 1H), 4.35-4.23 (m, 1H), 4.18-4.02 (m, 3H), 3.85 (d,J=14.6 Hz, 2H), 3.76 (dd, J=9.3, 3.7 Hz, 1H), 3.71-3.56 (m, 2H),3.27-3.24 (m, 4H), 3.17-2.98 (m, 3H), 2.89-2.70 (m, 2H), 2.55-2.41 (m,2H), 2.38-2.23 (m, 1H), 2.23-2.06 (m, 4H), 2.01-1.68 (m, 7H), 1.49 (s,9H), 1.46-1.38 (m, 1H), 1.24-1.09 (m, 6H). LCMS-ESI+ (m/z): calcd H+ forC₄₃H₅₈ClN₅O₇S: 824.37; found: 823.89.

Example 383

Example 383 was synthesized in the same manner as Example 75 usingExample 109 and methyl1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate. 1H NMR (400 MHz,Methanol-d4) δ 7.74 (d, J=8.5 Hz, 1H), 7.18 (dd, J=8.5, 2.4 Hz, 1H),7.14-7.06 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.90-6.84 (m, 1H), 6.68 (d,J=3.0 Hz, 1H), 6.54 (d, J=3.0 Hz, 1H), 6.02-5.89 (m, 1H), 5.58 (dd,J=15.2, 9.3 Hz, 1H), 4.44-4.29 (m, 1H), 4.12-4.00 (m, 5H), 3.88-3.53 (m,8H), 3.28-3.23 (m, 4H), 3.13-3.02 (m, 1H), 2.88-2.71 (m, 2H), 2.55-2.40(m, 2H), 2.37-2.24 (m, 1H), 2.24-2.06 (m, 4H), 2.01-1.66 (m, 7H),1.50-1.37 (m, 1H), 1.20-1.14 (m, 3H). LCMS-ESI+ (m/z): calcd H+ forC₄₂H₅₀ClN₅O₇S: 804.31; found: 803.76.

Example 384

To a stirred solution of Example 223 (10 mg, 0.014 mmol) in DCM (5 mL)was added isopropyl carbonochloridate (16.97 mg, 0.138 mmol) at 0° C.and stirred for 30 min and then to room temperature overnight. Thereaction mixture was evaporated and purified on reversed phasechromatography 0.1% TFA 70-95% acetonitrile to give Example 384. 1H NMR(400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.50(dd, J=8.3, 1.8 Hz, 1H), 7.20 (dd, J=8.5, 2.5 Hz, 1H), 7.10 (d, J=2.4Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.04 (dt, J=14.3, 6.5 Hz, 1H), 5.74(dd, J=15.8, 6.8 Hz, 1H), 5.17 (t, J=5.8 Hz, 1H), 4.86 (p, J=6.3 Hz,1H), 4.21-3.96 (m, 5H), 3.82 (s, 6H), 3.32 (d, J=14.5 Hz, 1H), 3.04 (dd,J=15.2, 10.0 Hz, 1H), 2.86-2.24 (m, 9H), 2.20-1.58 (m, 8H), 1.42 (t,J=10.3 Hz, 1H), 1.30 (dd, J=7.3, 6.2 Hz, 6H), 1.11 (d, J=6.8 Hz, 2H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₁H₅₀ClN₅O₈S: 808.31; found: 808.60.

Example 385

Example 385 was synthesized in the same manner as Example 75 usingtrans-azetidin-3-yl piperidine-1-carboxylate bis-trifluoroacetic acidand Example 109. 1H NMR (400 MHz, Methanol-d4) δ 7.72 (d, J=8.5 Hz, 1H),7.16 (d, J=9.2 Hz, 1H), 7.09 (d, J=6.2 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H),5.95 (dt, J=14.2, 6.7 Hz, 1H), 5.56 (dd, J=15.2, 9.1 Hz, 1H), 5.14-5.02(m, 1H), 4.38-4.25 (m, 3H), 4.14-4.01 (m, 2H), 3.97 (s, 1H), 3.83 (d,J=15.1 Hz, 1H), 3.74 (dd, J=9.3, 3.6 Hz, 1H), 3.65 (d, J=14.2 Hz, 1H),3.59 (dd, J=15.0, 5.7 Hz, 1H), 3.55-3.35 (m, 4H), 3.27 (d, J=14.4 Hz,1H), 3.24 (s, 3H), 3.06 (dd, J=15.3, 10.3 Hz, 1H), 2.85-2.65 (d, J=18.2Hz, 2H), 2.54-2.39 (m, 2H), 2.39-2.25 (m, 1H), 2.24-2.05 (m, 3H),1.99-1.49 (m, 8H), 1.44 (d, J=12.8 Hz, 1H), 1.13 (d, J=6.6 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₂H₅₅ClN₅O₇S: 808.34; found: 807.90.

Example 386

Step 1

Potassium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran,199 μL, 199 μmol) was added over 1 min via syringe to a stirred mixtureof Example 279 (30 mg, 40 μmol) and allyl bromide (20.7 μL, 239 μmol) intetrahydrofuran (2.0 mL) at −40° C. After 2 min, the resulting mixturewas warmed to room temperature. After 40 min, a solution of citric acid(100 mg) in water (10 mL) was added. Ethyl acetate (35 mL) was added,and the organic layer was washed sequentially with water (10 mL) and amixture of water and brine (1:1 v:v, 20 mL), dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was dissolved in tert-butyl alcohol (1.0 mL), water (0.5mL), and tetrahydrofuran (0.3 mL). The resulting mixture was stirred atroom temperature, and 4-methylmorpholine-N-oxide (9.9 mg, 85 μmol) andosmium tetroxide solution (2.5% wt. in tert-butyl alcohol, 50 μL, 4μmol) were added sequentially. After 90 min, sodium sulfite (83.2 mg,808 μmol) was added, and the resulting mixture was stirred vigorously.After 10 min, the resulting mixture was filtered through celite, and thefilter cake was extracted with ethyl acetate (25 mL) and dichloromethane(10 mL). The combined filtrates were washed sequentially with a mixtureof citric acid (100 mg) in water (10 mL) and brine (10 mL) and a mixtureof water and brine (1:1 v:v, 10 mL), dried over anhydrous magnesiumsulfate, filtered through celite, and concentrated under reducedpressure to give 386-1.

Step 2

Sodium periodate (23.3 mg, 109 μmol) was added to a vigorously stirredmixture of 386-1 (12 mg, 15 μmol), tetrahydrofuran (1.0 mL), and water(0.5 mL) at room temperature. After 45 min, ethyl acetate (30 mL) and asolution of citric acid (100 mg) in water (10 mL) were addedsequentially. The organic layer was washed with a mixture of water andbrine (1:1 v:v, 2×15 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue wasdissolved in toluene (3.0 mL), finely ground sarcosine (25.9 mg, 290μmol) was added, and the resulting mixture was stirred vigorously andwas heated to 120° C. After 45 min, the resulting mixture was cooled toroom temperature and was concentrated under reduced pressure. Theresidue was purified by reverse phase preparative HPLC (0.1%trifluoroacetic acid in acetonitrile/water) to give Example 386. 1H NMR(400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.37 (dd,J=8.3, 1.8 Hz, 1H), 7.26-7.16 (m, 2H), 7.13 (d, J=2.3 Hz, 1H), 6.93 (d,J=8.2 Hz, 1H), 6.12 (dd, J=15.4, 8.3 Hz, 1H), 5.92 (dd, J=15.4, 8.6 Hz,1H), 4.37-4.00 (m, 5H), 4.07 (s, 3H), 3.95-3.77 (m, 2H), 3.83 (s, 3H),3.72 (d, J=14.4 Hz, 1H), 3.56 (ddd, J=10.2, 6.0, 3.8 Hz, 1H), 3.42 (d,J=14.4 Hz, 1H), 3.38-3.19 (m, 2H), 3.18-3.07 (m, 1H), 2.93-1.59 (m,13H), 2.77 (s, 3H), 1.55-1.41 (m, 1H), 1.25 (d, J=6.9 Hz, 3H). LCMS:809.3.

Example 387

Example 387 was synthesized in the same manner as Example 75 usingtrans-azetidin-3-yl morpholine-4-carboxylate bis-trifluoroacetic acidand Example 109. 1H NMR (400 MHz, MeOH-d4) δ 7.72 (d, J=8.5 Hz, 1H),7.16 (dd, J=8.5, 2.4 Hz, 1H), 7.09 (dt, J=5.0, 2.1 Hz, 2H), 6.94-6.86(m, 2H), 5.95 (dt, J=14.3, 6.7 Hz, 1H), 5.56 (dd, J=15.3, 9.1 Hz, 1H),5.12 (tt, J=6.9, 4.0 Hz, 1H), 4.30 (m, 3H), 4.03 (dd, J=25.5, 6.3 Hz,4H), 3.83 (d, J=15.0 Hz, 1H), 3.74 (dd, J=9.2, 3.6 Hz, 1H), 3.71-3.56(m, 6H), 3.48 (d, J=24.7 Hz, 4H), 3.27 (d, J=14.4 Hz, 1H), 3.24 (s, 3H),3.05 (dd, J=15.3, 10.3 Hz, 1H), 2.89-2.67 (m, 2H), 2.55-2.39 (m, 2H),2.33 (q, J=9.0 Hz, 1H), 2.23-2.05 (m, 3H), 1.99-1.65 (m, 5H), 1.42 (t,J=13.8 Hz, 1H), 1.13 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcdfor C₄₁H₅₃ClN₅O₈S: 810.32; found: 809.82.

Example 388

Step 1: Synthesis of Intermediate 388-1

The mixture of 109-1-3 (155.0 mg, 0.498 mmol) and 109-1-4 (200 mg, 0.415mmol) in DCM (3.0 mL) at room temperature was treated with EDCI.HCl (159mg, 0.830 mmol) followed by DMAP (101 mg, 0.83 mmol). After stirred atroom temperature for overnight and reaction mixture was concentrated.The residue was dissolved in EtOAc (100.0 mL), washed with sat'd NH₄Cl,sat. NaHCO₃, brine, dried over sodium sulfate, filtered and concentratedto give 388-1. LCMS-ESI+ (m/z): calcd H+ for C₄₃H₅₂ClN₃O₆S: 774.33;found: 774.02.

Step 2: Synthesis of 388-2

388-1 was treated with a mixture of TFA (2.0 mL) and DCM (4.0 mL) atroom temperature for 1 hr. The reaction was then diluted with EtOAc,neutralized with sat. NaHCO₃ till pH˜7, washed with brine, dried oversodium sulfate, filtered and concentrated to give crude 388-2, purifiedby combiflash (12 g silica gel, 0-50% EtOAc/Hexanes). Desired fractionswere combined and concentrated, and treated with MeOH to give 388-2. 1HNMR (400 MHz, Methanol-d4) δ 7.67 (d, J=8.5 Hz, 1H), 7.55 (d, J=2.0 Hz,1H), 7.44 (dd, J=8.2, 1.9 Hz, 1H), 7.17-7.05 (m, 2H), 6.84 (d, J=8.2 Hz,1H), 5.78 (ddt, J=16.1, 10.8, 6.9 Hz, 1H), 5.57 (ddd, J=17.1, 10.5, 7.9Hz, 1H), 5.21-5.02 (m, 4H), 4.10-3.96 (m, 2H), 3.62 (dd, J=14.3, 4.4 Hz,1H), 3.58-3.48 (m, 3H), 3.37-3.34 (m, 1H), 3.31 (s, 1H), 2.84-2.66 (m,2H), 2.53 (pd, J=8.0, 4.0 Hz, 1H), 2.35-2.21 (m, 2H), 2.21-2.09 (m, 2H),2.08-1.92 (m, 3H), 1.91-1.81 (m, 2H), 1.81-1.47 (m, 4H), 1.13 (d, J=6.3Hz, 3H).

Step 3: Synthesis of 388-3

The solution of 388-2 (173 mg, 0.277 mmol) in DCE (35.0 mL) was degassedwith nitrogen. Hoveryda=Grubbs II catalyst (26.0 mg, 0.0415 mmol) wasadded, the resulting mixture was sparged with nitrogen for 3 moreminutes, and then it was capped and heated at 80° C. overnight undernitrogen balloon. The reaction was cooled to room temperature, mixedwith silica gel, concentrated to dryness, and purified by combiflash (12g silica gel, 0-60% EtOAc/Hexanes, dry loading). Desired fractions werecombined and concentrated to give 388-3. 1H NMR (400 MHz, Methanol-d4) δ7.77 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.2, 1.9 Hz, 1H), 7.19 (dd, J=8.5,2.4 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 6.86 (d,J=8.2 Hz, 1H), 6.02 (dt, J=14.1, 6.7 Hz, 1H), 5.56 (dd, J=15.4, 8.7 Hz,1H), 4.21 (dd, J=14.1, 6.8 Hz, 1H), 4.11-3.98 (m, 2H), 3.85 (d, J=14.9Hz, 1H), 3.77 (dd, J=8.8, 3.3 Hz, 1H), 3.69 (d, J=14.2 Hz, 1H), 3.27 (s,3H), 3.19-3.11 (m, 1H), 3.11-3.03 (m, 1H), 2.89-2.71 (m, 2H), 2.58-2.37(m, 3H), 2.29-2.20 (m, 1H), 2.17-2.08 (m, 2H), 2.00-1.87 (m, 4H),1.84-1.70 (m, 3H), 1.50-1.39 (m, 1H), 1.14 (d, J=6.8 Hz, 3H). LCMS-ESI+(m/z): calcd H+ for C₃₂H₄₀ClN₃O₄S:598.24; found: 598.03.

Step 4

To the mixture of 388-3 (70.0 mg, 0.117 mmol) and3-methoxy-1-methyl-pyrazole-4-carboxylic acid (36.5 mg, 0.234 mmol) inDCM (2.0 mL) at room temperature was added EDCI.HCl (44.7 mg, 0.234mmol) followed by DMAP (28.6 mg, 0.234 mmol). The resulting mixture wasstirred at room temperature for overnight. The reaction was thenconcentrated, redissolved in DMF (3.6 mL), filtered and purified byGilson reverse phase prep HPLC. Desired fractions were combined andconcentrated, frozen dried, triturated with acetonitrile, and filteredto give Example 388. 1H NMR (400 MHz, Methanol-d4) δ 8.04 (s, 1H), 7.76(d, J=8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 7.13(s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.16-6.04 (m, 1H), 5.64 (dd, J=15.5,8.1 Hz, 1H), 4.25-4.13 (m, 1H), 4.11-3.99 (m, 6H), 3.83-3.74 (m, 6H),3.30 (s, 3H), 3.17-3.13 (m, 1H), 2.91-2.76 (m, 2H), 2.66-2.40 (m, 5H),2.30-2.21 (m, 1H), 2.17-2.08 (m, 1H), 1.99-1.91 (m, 3H), 1.84-1.73 (m,3H), 1.53-1.41 (m, 1H), 1.20 (d, J=6.9 Hz, 3H). LCMS-ESI+ (m/z): calcdH+ for C₃₈H₄₆ClN₅O₆S: 736.29; found: 735.97.

Example 389

Example 389 was synthesized in a manner similar to Example 106 using3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid instead of2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid and using Example 5 insteadof 106-4. 1H NMR (400 MHz, Acetone-d6) δ 8.11 (s, 1H), 7.79 (d, J=8.5Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.42 (dd, J=8.2, 1.9 Hz, 1H), 7.26 (dd,J=8.5, 2.4 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 5.97(dt, J=15.7, 5.1 Hz, 1H), 5.85 (dd, J=15.9, 8.0 Hz, 1H), 4.13 (d, J=12.1Hz, 1H), 4.07 (s, 3H), 4.05-3.93 (m, 2H), 3.89 (d, J=13.5 Hz, 1H), 3.85(s, 3H), 3.80 (d, J=14.3 Hz, 1H), 3.59 (dd, J=7.9, 3.2 Hz, 1H), 3.49 (d,J=14.3 Hz, 1H), 3.27 (s, 3H), 3.23-3.14 (m, 1H), 3.01-1.55 (m, 16H),1.54-1.41 (m, 1H). LCMS: 722.1.

Example 390

Example 390 was synthesized in a manner similar to Example 244 usingExample 5 instead of 240-1. 1H NMR (400 MHz, Acetone-d6) δ 7.78 (d,J=8.5 Hz, 1H), 7.32-7.21 (m, 3H), 7.14 (d, J=2.4 Hz, 1H), 6.94 (d, J=8.1Hz, 1H), 5.98-5.87 (m, 1H), 5.79-5.69 (m, 1H), 4.36-4.16 (m, 3H), 4.12(d, J=12.1 Hz, 1H), 4.03 (d, J=12.1 Hz, 1H), 3.99-3.22 (m, 7H), 3.30 (s,3H), 3.24 (s, 3H), 3.17 (dd, J=15.2, 10.8 Hz, 1H), 2.95-1.55 (m, 16H),1.52-1.41 (m, 1H). LCMS: 697.1.

Example 391

Step 1

Selenium dioxide (261 mg, 2.36 mmol) was added to a vigorously stirredsolution of Example 5 (393 mg, 673 μmol) in 1,4-dioxane (6.7 mL) at roomtemperature, and the resulting mixture was heated to 80° C. After 10min, the resulting mixture was heated to 100° C. After 60 min, theresulting mixture was cooled to room temperature and was filteredthrough celite. The filter cake was extracted with dichloromethane (10mL), and the combined filtrates were concentrated under reducedpressure. The residue was purified by reverse phase preparative HPLC(0.1% trifluoroacetic acid in acetonitrile/water) to give 391-1 and391-2.

Step 2

Example 391 was synthesized in a manner similar to Example 106 using3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid instead of2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid and using 391-1 instead of106-4. 1H NMR (400 MHz, Acetone-d6) δ 8.11 (s, 1H), 7.94 (s, 1H), 7.79(d, J=8.6 Hz, 1H), 7.51-7.43 (m, 2H), 7.25 (dd, J=8.5, 2.4 Hz, 1H), 7.14(d, J=2.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 6.17-6.01 (m, 2H), 5.72 (d,J=4.8 Hz, 1H), 4.26 (dd, J=14.2, 7.0 Hz, 1H), 4.13 (d, J=12.1 Hz, 1H),4.10-3.70 (m, 4H), 4.08 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.69 (s,3H), 3.48 (d, J=14.4 Hz, 1H), 3.27 (s, 3H), 3.15 (dd, J=15.0, 10.9 Hz,1H), 2.93-1.54 (m, 14H), 1.54-1.43 (m, 1H). LCMS: 898.0 (M+Na)+.

Example 392

Potassium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran,27 μL, 27 μmol) was added over 1 min via syringe to a stirred mixture ofIntermediate 391-3 (4.0 mg, 5.4 μmol) and iodomethane (3.4 μL, 54 μmol)in tetrahydrofuran (1.0 mL) at −40° C. After 2 min, the resultingmixture was warmed to room temperature. After 7 min, trifluoroaceticacid (50 μL) was added, and the resulting mixture was concentrated underreduced pressure. The residue was purified by reverse phase preparativeHPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give Example392. 1H NMR (400 MHz, Acetone-d6) δ 8.11 (s, 1H), 7.77 (d, J=8.5 Hz,1H), 7.48 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.14(d, J=1.3 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.00 (dd, J=15.7, 7.2 Hz,1H), 5.89 (dd, J=15.7, 8.0 Hz, 1H), 4.14 (d, J=11.9 Hz, 1H), 4.11-4.04(m, 1H), 4.06 (s, 3H), 4.01 (d, J=12.1 Hz, 1H), 3.94-3.43 (m, 5H), 3.30(s, 3H), 3.26 (s, 3H), 3.16 (dd, J=14.8, 10.9 Hz, 1H), 2.96-1.63 (m,14H), 1.56-1.46 (m, 1H). LCMS: 752.2.

Example 393

Acetic anhydride (5.0 μL, 53 μmol) was added via syringe to a stirredmixture of Example 279 (4 mg, 5 μmol) and 4-(dimethylamino)pyridine (7.8mg, 64 μmol) in dichloromethane (0.6 mL) at room temperature, and theresulting mixture was heated to 45° C. After 30 min, the resultingmixture was cooled to room temperature and was concentrated underreduced pressure. The residue was purified by reverse phase preparativeHPLC (0.1% trifluoroacetic acid in acetonitrile/water) to give Example393. 1H NMR (400 MHz, Acetone-d6) δ 8.14 (s, 1H), 7.79 (d, J=8.5 Hz,1H), 7.48 (dd, J=8.3, 1.9 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.25 (dd,J=8.4, 2.4 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.13(dd, J=15.8, 5.4 Hz, 1H), 5.90 (dd, J=15.7, 7.4 Hz, 1H), 5.72 (s, 1H),4.18 (dd, J=15.2, 6.8 Hz, 1H), 4.11-4.03 (m, 2H), 4.09 (s, 3H),4.01-3.88 (m, 2H), 3.87 (s, 3H), 3.77 (d, J=14.4 Hz, 1H), 3.49 (d,J=14.3 Hz, 1H), 3.23 (s, 2H), 3.18 (dd, J=15.2, 10.4 Hz, 1H), 2.96-1.18(m, 17H), 1.12 (d, J=6.9 Hz, 3H). LCMS: 794.1.

Example 394

Example 394 was synthesized in a manner similar to Example 106 using3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid instead of2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid and using 391-2 instead of106-4. 1H NMR (400 MHz, Acetone-d6) δ 8.09 (s, 1H), 7.78 (d, J=8.5 Hz,1H), 7.45-7.39 (m, 2H), 7.24 (dd, J=8.6, 2.4 Hz, 1H), 7.12 (d, J=2.4 Hz,1H), 6.91 (d, J=8.1 Hz, 1H), 6.05 (dd, J=16.3, 7.9 Hz, 1H), 5.83 (dd,J=15.9, 5.0 Hz, 1H), 4.31-3.68 (m, 6H), 4.05 (s, 3H), 3.83 (s, 3H), 3.58(dd, J=8.3, 3.0 Hz, 1H), 3.45 (d, J=14.4 Hz, 1H), 3.36 (s, 3H), 3.28 (s,3H), 3.23-3.14 (m, 1H), 2.85-1.54 (m, 14H), 1.53-1.39 (m, 1H). LCMS:752.1.

Example 395 and Example 396

Preparation of Example 395 and Example 396: Potassiumbis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran, 66.5 μL,66.5 μmol) was added over 1 min via syringe to a stirred solution ofExample 279 (5.0 mg, 6.6 μmol) in tetrahydrofuran (0.6 mL) at −40° C.After 1 min, ACV-dimethylcarbamyl chloride (12.2 μL, 133 μmol) was addedvia syringe. After 2 min, the resulting mixture was warmed to roomtemperature. After 40 min, acetic acid (50 μL) and methanol (100 μL)were added sequentially, and the resulting mixture was concentratedunder reduced pressure. The residue was purified by reverse phasepreparative hplc (0.1% trifluoroacetic acid in acetonitrile/water) togive Example 395. 1H NMR (400 MHz, Acetone-d6) δ 8.43-7.66 (m, 2H),7.48-7.05 (m, 4H), 7.04-6.82 (m, 1H), 6.13-5.42 (m, 2H), 5.38-5.15 (m,1H), 4.34-3.10 (m, 17H), 3.10-1.18 (m, 28H). LCMS: 894.6. Furtherelution gave Example 396. 1H NMR (400 MHz, Acetone-d6) δ 8.20-6.65 (m,7H), 6.34-5.38 (m, 3H), 4.51-3.22 (m, 17H), 3.22-1.12 (m, 20H), 1.05 (d,J=7.1 Hz, 3H). LCMS: 823.0.

Example 397

Step 1

Dimethyl sulfate (8.54 mL, 90.2 mmol) was added via syringe to a stirredsolution of 4-iodo-1H-pyrazol-1-ol (3.79 g, 18.0 mmol) in chloroform (20mL) at room temperature. After 16 h, the resulting mixture was pouredinto diethyl ether (150 mL), and the resulting inhomogenous mixture wasswirled vigorously. The supernatant was decanted, and the residual gelwas dissolved in ethanol (19 mL) and stirred at room temperature.Triethylamine (8.33 mL, 59.8 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (375 mg, 512 μmol) were addedsequentially. The resulting mixture was placed under an atmosphere ofcarbon monoxide (1 atm) and was heated to 90° C. After 28 h, theresulting mixture was cooled to room temperature and was filteredthrough celite. The filter cake was extracted with a mixture of methanol(25 mL) and dichloromethane (50 mL). Potassium phosphate (14.5 g, 68.3mmol) was added to the combined filtrates, and the resultinginhomogeneous mixture was stirred vigorously. After 15 min, theresulting mixture was filtered through celite and was concentrated underreduced pressure. The residue was dissolved in a mixture ofdichloromethane (50 mL) and toluene (25 mL), basic alumina (30 g) wasadded, and the resulting slurry was concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel (0to 6% methanol in dichloromethane) to give 397-1.

Step 2

2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithium chloridecomplex solution (1.0 M in tetrahydrofuran/toluene, 3.85 mL, 3.85 mmol)was added via syringe to a stirred solution of 397-1 (131 mg, 770 μmol)in tetrahydrofuran (40 mL) at −40° C. After 3 h, a solution ofhexachloroethane (1.28 g, 5.39 mmol) in tetrahydrofuran (15 mL) wasadded via cannula. After 3 min, the resulting mixture was warmed to roomtemperature. After 4.5 h, silica gel (12 g) was added, and the resultingslurry was concentrated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel (0 to 5% methanol indichloromethane) to give impure 397-2. The impure material was purifiedby reverse phase preparative HPLC (0.1% trifluoroacetic acid inacetonitrile/water) to give 397-2.

Step 3

Sodium methoxide solution (25% wt. in methanol, 121 μL, 528 μmol) wasadded via syringe to a stirred solution of 397-2 (21.6 mg, 106 μmol) inmethanol (0.5 mL) at room temperature, and the resulting mixture washeated to 70° C. After 22 min, aqueous sodium hydroxide solution (2.0 M,158 μL, 317 μmol) was added via syringe. After 15 min, the resultingmixture was cooled to room temperature, and hydrogen chloride solution(4.0 M in 1,4-dioxane, 211 μL, 844 μmol) was added via syringe. Theresulting mixture was concentrated under reduced pressure. The residuewas dissolved in dichloromethane (1.0 mL) and was stirred at roomtemperature. 106-4 (10.0 mg, 16.7 μmol), 4-(dimethylamino)pyridine (20.4mg, 167 μmol), and3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (12.8 mg, 66.9 μmol) were added sequentially, and theresulting mixture was heated to 45° C. After 1 h, the resulting mixturewas cooled to room temperature and was concentrated under reducedpressure. The residue was purified by reverse phase preparative hplc(0.1% trifluoroacetic acid in acetonitrile/water) to give Example 397.1H NMR (400 MHz, Acetone-d6) δ 7.96-7.61 (m, 2H), 7.42-6.87 (m, 5H),6.15-6.00 (m, 1H), 5.69-5.50 (m, 1H), 4.27 (s, 3H), 4.25-3.24 (m, 7H),3.23 (s, 3H), 3.21-3.10 (m, 1H), 2.94-1.19 (m, 16H), 1.14 (d, J=6.1 Hz,3H). LCMS: 752.2.

Example 398

Step 1: Synthesis of 398-1

To a solution of Example 279 (20.0 mg, 0.0266 mmol) in DMF (1.0 mL) atroom temperature was added allyl bromide (19.3 mg, 0.16 mmol) followedby 60% NaH dispersion in mineral oil (6.38 mg, 0.16 mmol). The reactionwas heated at 50° C. for 90 min. LCMS showed about −50% conversion.Additional allyl bromide (19.3 mg, 0.16 mmol) and 60% NaH dispersion inmineral oil (6.38 mg, 0.16 mmol) were added, heated at 50° C. foranother 90 min. The reaction was quenched with sat. NH₄Cl, washed withbrine, dried over sodium sulfate, filtered, and concentrated to give398-1. LCMS-ESI+ (m/z): calcd H+ for C₄₁H₅₀ClN₅O₇S: 792.31; found:792.03.

Step 2: Synthesis of 398-2

398-1 (21.0 mg, 0.0265 mmol) was dissolved in a mixture of tBuOH (1.0mL), THF (0.3 mL) and water (0.5 mL) at room temperature. NaIO4 (42.5mg, 0.199 mmol) was added followed by 2.5% OsO4 in tBuOH (33.2 uL,0.0027 mmol). The resulting mixture was stirred at room temperature for90 minutes. The reaction was quenched with 1 N sodium thiosulfate,stirred vigorously at room temperature for 10 min, extracted with EtOAc(2×20 mL). Combined organic layer was washed with brine, dried oversodium sulfate, filtered, and concentrated to give 398-2. LCMS-ESI+(m/z): calcd H+ for C₄₀H₄₈ClN₅O₈S: 794.29; found: 793.96.

Step 3: Synthesis of Example 398

To the mixture of 398-2 and(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine;dihydrochloride (11.4 mg, 0.053 mmol) in DCE (1.0 mL) at roomtemperature was added DIEA (6.83 mg, 0.053 mmol). The resulting mixturewas stirred for 5 minutes, STAB (11.2 mg, 0.053 mmol) was added, and thereaction was stirred for overnight. The reaction was concentrated,re-dissolved in DMF (1.2 mL) and water (0.6 mL), filtered and purifiedby reverse phase prep HPLC (40-90% ACN/H2O with 0.1% TFA). The desiredfractions were combined and frozen dried to give Example 398. 1H NMR(400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.38 (dd,J=8.2, 1.9 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.5, 2.4 Hz,1H), 7.13 (d, J=2.3 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.18 (dd, J=15.4,8.5 Hz, 1H), 5.92 (dd, J=15.4, 8.8 Hz, 1H), 4.26 (dd, J=15.0, 5.1 Hz,1H), 4.13-4.04 (m, 7H), 3.94-3.78 (m, 9H), 3.75-3.59 (m, 4H), 3.46-3.36(m, 4H), 3.31 (s, 3H), 3.23-3.09 (m, 3H), 2.90-2.76 (m, 4H), 2.70-2.47(m, 5H), 2.36-2.25 (m, 1H), 2.12 (d, J=13.6 Hz, 1H), 2.02-1.88 (m, 3H),1.83 (d, J=7.4 Hz, 3H), 1.53-1.41 (m, 1H), 1.24 (d, J=6.9 Hz, 3H).LCMS-ESI+ (m/z): calcd H+ for C₄₇H₆₂ClN₇O₈S: 920.41; found: 920.45.

Example 399 Step 1: Synthesis of 399-1

Intermediate 399-1 (22.0 mg, 0.0358 mmol) and5-formyl-1-methyl-pyrrole-3-carboxylic acid (11.0 mg, 0.0716 mmol) weredissolved in DCM (2.0 mL) at room temperature, EDCI.HCl (13.7 mg, 0.0716mmol) was added followed by DMAP (8.75 mg, 0.0716 mmol). The resultingmixture was stirred for 1 hr. The reaction was concentrated,re-dissolved in EtOAc, the organic layer was washed sequentially withsat. NH₄Cl, sat. NaHCO₃, and brine, dried over sodium sulfate, filtered,and concentrated to give 399-1. LCMS-ESI+ (m/z): calcd H+ forC₃₉H₄₅ClN₄O₇S: 749.27; found: 748.96.

Step 2: Synthesis of 399-2

399-1 was dissolved in DMF (1.0 mL) at room temperature; Mel (21.4 mg,0.151 mmol) was added followed by 60% NaH dispersion in mineral oil(6.02 mg, 0.151 mmol). The resulting mixture was heated at 50° C. for 30min, and the reaction was then cooled to room temperature, diluted withDMF (0.5 mL), filtered, and purified by reverse phase prep HPLC. Desiredfractions were combined and frozen dried to give 399-2. LCMS-ESI+ (m/z):calcd H+ for C₄₀H₄₇ClN₄O₇S 763.29; found: 762.98.

Step 3

To the stirred mixture of 399-2 (28 mg, 0.037 mmol) and(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine;dihydrochloride (11.8 mg, 0.055 mmol) in DCE (1.0 mL) at roomtemperature was added DIEA (16.6 mg, 0.128 mmol). The resulting mixturewas stirred for 5 minutes before STAB (11.7 mg, 0.055 mmol) was added.The newly formed mixture was then stirred at room temperature forovernight, and then concentrated, re-dissolved in DMF (1.2 mL),filtered, and purified by reverse phase prep HPLC. Desired fractionswere combined and frozen dried to give Example 399. LCMS-ESI+ (m/z):calcd H+ for C₄₇H₆₁ClN₆O₇S: 889.40; found: 889.19. 1H NMR (400 MHz,Methanol-d4) δ 7.69 (d, J=1.9 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.34 (dd,J=8.3, 1.8 Hz, 1H), 7.05 (dd, J=9.9, 2.1 Hz, 2H), 6.91-6.78 (m, 3H),6.21-6.11 (m, 1H), 5.68 (dd, J=15.3, 8.3 Hz, 1H), 4.14 (dd, J=14.7, 6.7Hz, 1H), 4.06-3.88 (m, 7H), 3.84-3.72 (m, 7H), 3.64 (d, J=14.5 Hz, 1H),3.47-3.42 (m, 1H), 3.25-3.09 (m, 5H), 3.06-2.65 (m, 8H), 2.58-2.34 (m,3H), 2.34-2.14 (m, 4H), 2.08 (d, J=13.6 Hz, 1H), 2.02-1.78 (m, 6H),1.42-1.35 (m, 1H), 1.16 (d, J=6.2 Hz, 3H).

Example 400

Example 279 (10 mg, 0.014 mmol) was dissolved in a 1:1 mixture ofdichlormethane and H₂O (0.15 mL: 0.15 mL). Potassium bifluoride (15 mg)was added as a solid. The reaction was stirred at room temperature for 2min before (bromodifluoromethyl)trimethylsilane was added (50 μL). Thereaction was heated to 50° C. for 8 hours before it was cooled to roomtemperature. The reaction mixture was purified directly by Gilsonreverse phase prep HPLC (60-100% ACN/H₂O with 0.1% TFA) to give Example400. ¹H NMR (400 MHz, Methanol-d₄) δ 8.09 (s, 1H), 7.77 (d, J=8.4 Hz,1H), 7.43-7.37 (m, 1H), 7.24 (s, 1H), 7.21-7.14 (m, 1H), 7.12 (d, J=2.2Hz, 2H), 6.92 (t, J=ID Hz, 1H), 6.44 (s, 1H), 6.18 (dd, J=15.5, 6.1 Hz,1H), 5.93 (dd, J=15.2, 8.2 Hz, 1H), 4.16-3.99 (m, 8H), 3.89 (m, 2H),3.82 (m, 4H), 3.73 (d, J=13.9 Hz, 1H), 3.41 (d, J=14.3 Hz, 1H), 3.28 (s,3H), 3.15 (m, 1H), 2.83 (m, 2H), 2.52 (m, 1H), 2.40 (m, 1H), 2.08 (m,1H), 1.92 (m, 2H), 1.79 (m, 3H), 1.33 (m, 1H), 1.19 (d, J=6.8 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₃₉H₄₅ClF₂N₅O₇S: 802.3; found: 802.5.

Example 401

Example 401 was synthesized in the same manner as Example 283 using2-bromo-N,N-dimethylacetamide and Example 279. ¹H NMR (400 MHz,Methanol-d₄) δ 8.11 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.36 (dd, J=8.2,1.9 Hz, 1H), 7.23-7.08 (m, 3H), 6.91 (d, J=8.2 Hz, 1H), 6.06 (dd,J=15.5, 7.6 Hz, 1H), 5.89 (dd, J=15.5, 8.5 Hz, 1H), 4.26 (d, J=13.9 Hz,1H), 4.19-4.00 (m, 9H), 3.92-3.84 (m, 2H), 3.82 (s, 3H), 3.72 (d, J=14.3Hz, 1H), 3.41 (d, J=14.4 Hz, 1H), 3.35 (m, 2H), 3.31 (s, 3H), 3.17-3.07(m, 1H), 2.99 (s, 3H), 2.88 (s, 3H), 2.86-2.71 (m, 1H), 2.52 (m, 2H),2.36 (m, 1H), 2.11 (d, J=13.6 Hz, 1H), 1.96 (m, 2H), 1.82 (d, J=7.0 Hz,3H), 1.47 (d, J=13.6 Hz, 1H), 1.23 (d, J=6.9 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₄₂H₅₃ClN₆O₈S: 837.3; found: 837.9.

Example 402

Example 402 was synthesized in the same manner as Example 283 using2-(chloromethyl)pyridine and Example 279. ¹H NMR (400 MHz, Methanol-d₄)δ 8.71 (d, J=5.7 Hz, 1H), 8.37 (t, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.94 (d,J=7.9 Hz, 1H), 7.85-7.80 (m, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.40-7.35 (m,1H), 7.23-7.11 (m, 4H), 6.94 (d, J=8.2 Hz, 1H), 6.15 (dd, J=15.6, 7.6Hz, 1H), 5.99 (dd, J=15.5, 8.3 Hz, 1H), 4.82-4.69 (m, 1H), 4.32-4.10 (m,4H), 4.07 (s, 3H), 3.92-3.84 (m, 3H), 3.83 (s, 3H), 3.79-3.68 (m, 2H),3.41 (d, J=14.3 Hz, 1H), 3.28 (s, 3H), 3.21-3.01 (m, 2H), 2.87-2.75 (m,2H), 2.66-2.34 (m, 3H), 2.11 (m, 1H), 1.96 (m, 2H), 1.83 (m, 3H), 1.47(s, 1H), 1.26 (d, J=6.9 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd forC₄₄H₅₁ClN₆O₇S: 843.3; found: 843.2.

Example 403

Example 279 (10 mg, 0.014 mmol) was dissolved in DMF (0.15 mL). Sodiumhydroxide (excess, 1 pellet) was added as a solid. The reaction washeated to 50° C. for 8 hours before it was cooled to room temperature.The reaction mixture was purified directly by Gilson reverse phase prepHPLC (40-90% ACN/H₂O with 0.1% TFA) to give Example 403. ¹H NMR (400MHz, Methanol-d₄) δ 8.08 (s, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.37 (dd,J=8.2, 1.8 Hz, 1H), 7.25-7.17 (m, 2H), 7.13 (d, J=2.3 Hz, 1H), 6.93 (d,J=8.3 Hz, 1H), 6.15 (dd, J=15.4, 8.7 Hz, 1H), 5.94 (dd, J=15.3, 8.7 Hz,1H), 4.23 (dd, J=14.9, 4.3 Hz, 1H), 4.16-4.02 (m, 8H), 3.86 (d, J=9.8Hz, 6H), 3.82 (s, 3H), 3.75-3.61 (m, 2H), 3.46-3.38 (m, 2H), 3.33-3.28(m, 2H), 3.20-3.09 (m, 1H), 2.96 (m, 6H), 2.89-2.75 (m, 2H), 2.62-2.46(m, 2H), 2.29 (m, 1H), 2.12 (d, J=13.7 Hz, 1H), 1.96 (m, 2H), 1.84 (m,3H), 1.46 (d, J=10.5 Hz, 1H), 1.26 (d, J=6.9 Hz, 3H). LCMS-ESI+ (m/z):[M+H]+ calcd for C₄₂H₅₅ClN₆O₇S: 823.4; found: 823.4.

Example 404

To a stirred solution of Example 223 (10 mg, 0.014 mmol) indimethylcarbamic chloride (2 mL) was added DMAP (16 mg, 0.138 mmol) andstirred for at 80° C. overnight. The solvent was evaporated, and thereaction mixture was purified on reversed phase chromatography 0.1% TFA70-95% acetonitrile to give Example 404 ¹H NMR (400 MHz, Chloroform-d) δ7.83 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.49 (dd, J=8.2, 1.9 Hz, 1H), 7.43(d, J=2.0 Hz, 1H), 7.19 (dd, J=8.5, 2.3 Hz, 1H), 7.10 (d, J=2.3 Hz, 1H),6.93 (d, J=8.2 Hz, 1H), 5.89 (dt, J=13.3, 6.4 Hz, 1H), 5.73 (dd, J=15.7,5.4 Hz, 1H), 5.26 (t, J=5.6 Hz, 1H), 4.18-3.97 (m, 5H), 3.82 (s, 3H),3.71 (d, J=14.5 Hz, 2H), 3.33 (d, J=14.6 Hz, 1H), 3.06 (dd, J=15.3, 9.0Hz, 1H), 2.93-2.63 (m, 7H), 2.61-2.47 (m, 2H), 2.43-1.55 (m, 11H), 1.41(dd, J=23.1, 10.6 Hz, 2H), 1.28 (s, 1H), 1.14 (d, J=6.8 Hz, 3H).LCMS-ESI+ (m/z): [M+H]+ calcd for C₄₀H₄₉ClN₆O₇S: 793.31; found: 792.58.

Examples 405-464 were synthesized by the methods described herein.

LCMS- ESI+ LCMS-ESI+ (m/z): (m/z): [M + H]+ [M + H]+ Example Structurecalcd found 405

706.28 706.19 406

754.3 754.3 407

726.3 726.1 408

762.3 762.1 409

693.24 692.92 410

746.3 746.1 411

709.22 708.96 412

743.3 743.15 413

719.3 719 414

695.3 694.7 415

745.31 745.31 416

758.34 758.82 417

796.34 796.2 418

811.34 811.05 419

746.3 746.1 420

733.31 734.33 421

669.28 668.76 422

721.3 720.98 423

695.3 694.78 424

748.293 747.68 425

746.31 746.03 426

743.3 743.11 427

696.2869 695.95 428

697.2821 696.92 429

764.25 763.93 430

758.3 758.2 431

746.28 745.97 432

743.29 743.24 433

695.3 695.2 434

722.24 721.86 435

750.33 750.14 436

720.3 720.4 437

771.31 770.75 438

753.3083 753.02 439

753.3083 753.07 440

717.2684 716.71 441

718.28 718.01 442

725.31 724.69 443

732.29 732.21 444

722.24 723.209 445

696.3 695.9 446

708.28 708.23 447

708.28 708.23 448

756.3 756.9 449

723.3 723.6 450

757.2933 757.1 451

791.32 791.2 452

711.3 710.66 453

779.28 778.68 454

655.26 655.79 455

846.2732 846.1 456

737.31 736.79 457

746.31 745.82 458

734.2774 734.1 459

794.2985 794.1 460

748.293 748.2 461

718.2824 718.1 462

819.3301 819.1 463

774.3087 774.61 464

791.33 791.28MCL-1/Bim Binding AlphaLISA Assay.

Inhibition of the MCL-1 and Bim interaction was measured in thefollowing AlphaLISA assay.

Materials

Recombinant human MCL-1 protein (C-terminal 6×His Tagged Mcl-1containing residues 171-327) was generated at Gilead Sciences, Inc.(Foster City, Calif.). A biotinylated peptide derived from human Bim(residues 51-76) was purchased from CPC Scientific (Sunnyvale, Calif.).(CPC 834113). AlphaLISA anti-6His-acceptor beads (AL128R), AlphaScreenStreptavidin donor beads (6760002B), and Proxiplate-384 Plus (6008289)were purchased from PerkinElmer.

Methods

The AlphaLISA assay was performed in a 384-well Proxiplate in a totalvolume of 40 μL. The reaction mixture contained 0.0625 nM 6×His-Mcl-1(171-327), 0.0625 nM biotinylated-Bim peptide, 10 μg/mL AlphaLISAanti-6×His-AlphaLISA acceptor beads, 40 μg/mL AlphaScreen streptavidindonor beads, and serially diluted test compounds in the binding buffer(20 mM Hepes, pH 7.5 (Teknova H1035); 150 mM NaCl (Promega V4221);0.002% Brij 35 (Thermo Scientific 20150); 1 mM Dithiothreitol (DTT)Solution (Affymetrix 70726); 0.01% BSA (BioLabs B9000S)). 1,000× testcompounds were pre-spotted onto 384-well Proxiplate (Labcyte Echo) byEcho 555 Liquid Handler (Labcyte Inc., San Jose, Calif.) followed byincubation of 5 μl Mcl-1 (171-327) for 1 hour. Then 5 μL Bim (51-76) wasadded and incubated for 2 hours. Five μL AlphaLISA anti-6His-AlphaLISAacceptor beads were then added for 1 hour followed by addition of 5 μLAlphaScreen streptavidin donor beads for 1 hour. The reaction plateswere then read on an Envision multimode reader (PerkinElmer) usingAlphaScreen settings. IC₅₀ values were calculated and reported inTable 1. Comparative Example 1 is Example 4 from InternationalPublication No. WO 2016/033486). Percent inhibition was calculated asshown below:% Inhibition=100%*(Well−Neg)/(Pos−Neg)Neg: negative control, DMSOPos: positive control, no Mcl-1 protein, no biotinylated-Bim peptide

TABLE 1 MCL-1/Bim IC₅₀ (nM) Example IC₅₀ (nM) 1 0.9 2 1.5 3 4.1 4 0.7 560.2 6 27.3 7 1.2 8 0.7 9 6.6 10 3.6 11 6.5 12 1.7 13 1.8 14 0.3 15 7.416 4.2 17 11.3 18 0.3 19 1.1 20 0.5 21 0.8 22 0.1 23 0.8 24 0.2 25 0.626 1.8 27 1.6 28 0.2 29 0.6 30 0.6 31 3.1 32 1.4 33 2.9 34 2.0 35 0.2 368.1 37 1.4 38 0.2 39 0.1 40 0.1 41 0.1 42 0.1 43 1.6 44 0.1 45 0.1 460.1 47 0.1 48 3.7 49 0.1 50 1.4 51 0.1 52 0.9 53 0.2 54 0.2 55 0.2 560.6 57 0.2 58 0.2 59 0.1 60 0.2 61 0.1 62 0.4 63 1.4 64 5.2 65 1.8 662.7 67 1.2 68 46.9 69 4.0 70 0.2 71 0.7 72 0.1 73 0.3 74 7.3 75 0.3 7610.5 77 5.3 78 0.8 79 0.4 80 0.3 81 0.5 82 1.1 83 0.1 84 0.1 85 0.6 861.8 87 3.2 88 1.5 89 0.5 90 0.5 91 0.1 92 0.1 93 51.0 94 0.9 95 1.1 960.4 97 0.6 98 0.3 99 0.2 100 0.2 101 1.4 102 0.3 103 1.0 104 0.1 105 0.1106 0.1 107 0.1 108 0.1 109 10.643 110 2.634 111 0.093 112 0.047 1130.046 114 0.043 115 0.068 116 0.08 117 0.113 118 0.103 119 0.145 1200.167 121 0.163 122 0.161 123 0.071 124 0.066 125 0.074 126 0.099 1270.085 128 0.068 129 0.077 130 0.18 131 0.046 132 0.038 133 0.051 1340.072 135 0.213 136 0.183 137 0.491 138 0.112 139 0.116 140 0.043 1410.086 142 0.097 143 0.173 144 0.05 145 0.037 146 0.062 147 0.051 1480.043 149 0.109 150 0.071 151 0.036 152 0.057 153 0.086 154 0.05 1550.060 156 0.111 157 0.234 158 0.135 159 0.087 160 0.031 161 0.025 1620.180 163 0.263 164 0.141 165 0.035 166 0.067 167 0.141 168 0.222 1690.048 170 0.060 171 0.033 172 0.022 173 0.087 174 0.153 175 0.140 1760.138 177 0.129 178 0.141 179 0.102 180 0.092 181 0.146 182 0.144 1830.132 184 0.108 185 0.041 186 0.066 187 0.107 188 0.069 189 0.033 1900.055 191 0.103 192 0.054 193 0.046 194 0.030 195 0.036 196 0.040 1970.041 198 0.043 199 0.117 200 0.064 201 0.042 202 0.082 203 0.073 2040.048 205 0.075 206 0.047 207 0.162 208 0.136 209 0.202 210 0.071 2110.082 212 0.040 213 0.076 214 0.185 215 0.203 216 0.196 217 0.065 2180.345 219 0.099 220 0.122 221 0.046 222 0.044 223 0.039 224 0.195 2250.043 226 0.095 227 0.076 228 0.069 229 0.030 230 0.027 231 0.051 2320.052 233 0.016 234 0.053 235 0.035 236 0.055 237 0.044 238 0.033 2390.042 240 0.018 241 0.087 242 0.074 243 0.059 244 0.032 245 0.066 2460.096 247 0.042 248 0.042 249 0.140 250 0.029 251 0.037 252 0.043 2530.037 254 0.126 255 0.096 256 0.162 257 0.083 258 0.117 259 0.098 2600.061 261 0.053 262 0.056 263 0.073 264 0.263 265 0.046 266 0.085 2670.030 268 0.058 269 0.081 270 0.041 271 0.100 272 0.018 273 0.077 2740.043 275 0.053 276 0.068 277 0.061 278 0.089 279 0.041 280 0.044 2810.154 282 0.086 283 0.029 284 0.061 285 0.131 286 0.037 287 0.029 2880.144 289 0.053 290 0.030 291 0.039 292 0.020 293 0.058 294 0.129 2950.040 296 0.053 297 0.033 298 0.016 299 0.039 300 0.026 301 0.040 3020.091 303 0.045 304 0.129 305 0.088 306 0.057 307 0.120 308 0.031 3090.029 310 0.074 311 0.024 312 0.039 313 0.064 314 0.054 315 0.127 3160.056 317 0.034 318 0.066 319 0.038 320 0.035 321 0.037 322 0.057 3230.158 324 0.058 325 0.100 326 0.076 327 0.051 328 0.049 329 0.087 3300.030 331 0.075 332 0.071 333 0.039 334 0.041 335 0.235 336 0.100 3370.050 338 0.090 339 0.070 340 0.031 341 0.032 342 0.029 343 0.019 3440.049 345 0.037 346 0.031 347 0.084 348 0.041 349 0.026 350 0.055 3510.035 352 0.046 353 0.103 354 0.039 355 0.062 356 0.081 357 0.113 3580.114 359 0.038 360 0.052 361 0.055 362 0.024 363 0.042 364 0.064 3650.040 366 0.086 367 0.063 368 369 370 371 372 373 374 0.058 375 0.046376 0.031 377 0.106 378 1.152 379 0.834 380 4.539 381 0.769 382 1.400383 0.659 384 0.340 385 0.128 386 0.048 387 0.102 388 1.065 389 0.075390 0.061 391 0.702 392 0.070 393 0.062 394 1.718 395 5.267 396 3970.045 398 399 0.070 400 0.058 401 0.044 402 0.098 403 0.059 404 0.092405 0.113 406 0.103 407 0.113 408 0.054 409 0.147 410 0.194 411 0.178412 0.072 413 0.478 414 0.217 415 0.526 416 0.047 417 0.092 418 0.197419 0.186 420 0.237 421 0.081 422 0.035 423 0.056 424 0.037 425 0.078426 0.091 427 0.104 428 0.069 429 0.129 430 0.170 431 0.121 432 0.070433 0.133 434 0.446 435 0.114 436 0.886 437 0.301 438 0.187 439 0.138440 0.051 441 0.223 442 0.134 443 0.187 444 0.101 445 0.091 446 0.149447 0.132 448 0.117 449 0.131 450 0.234 451 0.520 452 0.045 453 0.092454 0.098 455 0.147 456 0.099 457 0.085 458 0.079 459 0.085 460 0.089461 0.087 462 0.251 463 0.219 464 0.209 Comparative Example 1 0.5SKBR3 Cell Viability AssayMaterials

SKBR3 Cells (ATCC HTB-30) were obtained from ATCC (Manassas, Va.) andcultured in McCoy 5A's medium (ATCC 30-2007)+10% fetal bovine serum(SH30071.03, HyClone, Pittsburgh, Pa.) plus 1× Penicillin-StreptomycinL-glutamine (Corning 30-009-C1, Corning, N.Y.)).

Methods

The cell viability assay was conducted in a 384-well tissue cultureplate (Grenier 781086, Monroe, N.C.) in a total volume of 70 μL. Testcompounds were prepared in 1,000×, serially diluted, and pre-spottedinto 384-well tissue culture plate by Echo 555 Liquid Handler (LabcyteInc., San Jose, Calif.). Seventy pi of 6,000 SKBR3 cells were dispensedinto each well of the plate and incubated at 37° C. with 5% CO₂ for 72hours. At the end of incubation, 2× CellTiter Glo (CTG) reagents (1 partbuffer with 2 parts substrate) (Promega, Madison, Wis.) were prepared,and the plate and the reagent were equilibrated to room temperature for30 minutes. CTG reagent was added to each plate by Biomek FX at 20μL/well with 5 times pipetting and mixing to induce cell lysis.Luminescence was read by Envision multimode reader (PerkinElmer). EC₅₀values were calculated and reported in Table 2. Comparative Example 1 isExample 4 from International Publication No. WO 2016/033486). Percentinhibition was calculated as followed:% Inhibition=100%*(Well−Neg)/(Pos−Neg)Neg, negative control, DMSOPos, positive control, 10 μM Puromycin

TABLE 2 MCL-1 CV SKBR3 EC₅₀ (nM) Example EC₅₀ (nM) 1 1701.8 2 792.2 3N.D. 4 899.1 5 10000.0 6 8731.8 7 4800.1 8 N.D. 9 7776.1 10 N.D. 1110000.0 12 4464.8 13 3274.3 14 356.3 15 7734.0 16 10000.0 17 10000.0 18894.5 19 1084.8 20 2060.5 21 1303.0 22 259.4 23 1451.0 24 891.2 252005.9 26 1685.9 27 2080.3 28 8407.1 29 1838.6 30 1835.7 31 2585.3 321478.8 33 7436.2 34 3354.6 35 265.7 36 10000.0 37 1612.6 38 280.0 39261.6 40 328.0 41 255.5 42 3338.7 43 2410.8 44 375.6 45 191.2 46 512.347 758.2 48 8453.2 49 207.2 50 3320.5 51 705.4 52 1951.8 53 388.1 543809.1 55 685.2 56 1180.4 57 596.5 58 663.5 59 873.9 60 1090.8 61 774.862 2427.2 63 9713.3 64 5825.9 65 1971.3 66 5828.7 67 1040.8 68 6299.0 697800.5 70 373.6 71 1385.7 72 262.0 73 2449.3 74 10000.0 75 691.7 766330.5 77 6036.1 78 4068.4 79 3031.6 80 1059.2 81 612.3 82 2315.0 83460.5 84 783.2 85 3092.7 86 4913.7 87 10000.0 88 2571.9 89 854.8 904557.9 91 616.1 92 245.0 93 4822.2 94 901.6 95 1103.0 96 603.6 97 787.798 2188.5 99 2091.9 100 2260.5 101 2586.5 102 891.3 103 10000.0 104 N.D.105 351.4 106 N.D. 107 N.D. 108 N.D. 109 110 111 721.43 112 73.25 113114 154.23 115 116 141.46 117 82.89 118 184.35 119 93.75 120 106.06 12171.54 122 112.69 123 114.49 124 95.85 125 88.65 126 122.98 127 157.55128 96.44 129 64.66 130 152.35 131 161.74 132 71.99 133 130.07 134 59.56135 131.91 136 76.42 137 103.58 138 60.54 139 94.07 140 38.59 141 65.32142 416.33 143 218.95 144 50.76 145 147.42 146 184.91 147 110.61 14837.17 149 95.28 150 39.26 151 152 55.70 153 69.50 154 24.1 155 43.01 156145.374 157 64.776 158 47.436 159 144.479 160 35.036 161 168.251 162136.473 163 98.741 164 106.452 165 45.503 166 79.778 167 58.568 16874.154 169 60.981 170 209.553 171 129.805 172 125.128 173 67.868 174102.675 175 33.867 176 79.254 177 46.373 178 143.607 179 82.519 180134.333 181 37.915 182 136.147 183 195.116 184 47.24 185 99.209 186167.95 187 43.096 188 78.259 189 64.255 190 191 123.213 192 39.714 193194 195 29.64 196 99.186 197 129.808 198 103.987 199 58.219 200 201103.304 202 90.982 203 76.148 204 136.301 205 58.879 206 207 43.957 20845.025 209 210 43.444 211 54.2 212 37.619 213 56.973 214 55.876 215 216217 83.199 218 85.531 219 145.684 220 97.761 221 103.725 222 80.097 22337.34 224 83.461 225 51.277 226 71.326 227 21.252 228 69.861 229 23047.091 231 39.981 232 242.625 233 47.175 234 73.857 235 39.785 236151.512 237 120.97 238 23.352 239 240 91.536 241 242 83.993 243 41.72244 116.254 245 60.739 246 176.397 247 84.985 248 55.287 249 221.575 25044.38 251 39.574 252 82.721 253 39.167 254 154.781 255 256 160.518 25789.674 258 194.681 259 260 261 72.01 262 85.774 263 62.236 264 26596.236 266 53.788 267 184.308 268 88.772 269 264.075 270 61.679 271175.649 272 47.923 273 81.006 274 82.551 275 90.367 276 64.262 27760.866 278 80.523 279 280 50 281 183.521 282 28.657 283 84.797 28454.672 285 79.68 286 65.07 287 25.014 288 169.57 289 588.134 290 26.375291 292 45.095 293 69.205 294 260.141 295 21.969 296 64.086 297 68.966298 71.896 299 59.742 300 26.776 301 41.854 302 301.941 303 22.84 30421.302 305 139.57 306 43.594 307 96.799 308 16.109 309 10.548 310230.419 311 13.432 312 43.55 313 94.474 314 32.934 315 164.107 316115.522 317 48.506 318 74.379 319 19.879 320 36.615 321 47.093 32264.447 323 169.714 324 37.906 325 50.295 326 52.579 327 28.609 32872.183 329 56.983 330 56.423 331 68.944 332 51.133 333 38.306 334 48.609335 66.239 336 60.424 337 86.397 338 123.754 339 53.182 340 37.086 34139.429 342 33.638 343 17.328 344 18.544 345 22.56 346 30.944 347 79.756348 84.676 349 33.724 350 75.591 351 58.806 352 54.429 353 256.743 35436.948 355 67.355 356 233.261 357 206.237 358 95.129 359 19.022 360139.487 361 44 362 17.259 363 46.531 364 258.689 365 145.67 366 53.129367 100.501 368 369 370 5795.45 371 372 373 374 47.482 375 22.367 37626.706 377 33.992 378 1182.46 379 1663.07 380 3401.06 381 534.464 382562.153 383 1195.62 384 153.799 385 221.972 386 83.761 387 161.643 3881395.31 389 303.742 390 86.369 391 4557.45 392 142.343 393 33.351 3944745.65 395 6177.74 396 397 398 399 19.98 400 530.34 401 117.941 40290.153 403 13.758 404 196.712 405 195.953 406 332.427 407 408 240.875409 297.308 410 145.606 411 174.67 412 179.346 413 129.529 414 153.743415 104.739 416 130.943 417 403.335 418 335.297 419 135.182 420 124.328421 152.44 422 187.244 423 168.533 424 147.23 425 170.703 426 316.412427 331.872 428 164.693 429 260.617 430 139.281 431 233.147 432 171.684433 394.987 434 402.832 435 167.159 436 752.744 437 122.588 438 278.341439 789.246 440 284.088 441 373.917 442 122.053 443 161.763 444 171.572445 209.764 446 175.783 447 161.434 448 250.704 449 146.579 450 167.379451 160.647 452 282.052 453 96.749 454 146.083 455 145.824 456 174.228457 391.672 458 376.136 459 194.159 460 461 151.118 462 344.509 463 464222.449 Comparative Example 1 2190.4

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure. The descriptionis made with the understanding that it is to be considered anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated. Theheadings used throughout this disclosure are provided for convenienceand are not to be construed to limit the claims in any way. Embodimentsillustrated under any heading may be combined with embodimentsillustrated under any other heading.

The invention claimed is:
 1. A compound according to Formula (Ia):

or a pharmaceutically acceptable salt thereof; wherein:

is a single or double bond; X is O or NR⁷; R¹² is hydrogen or —C(O)R¹;R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocyclyl, 5-10 memberedheteroaryl, —OR⁷, or —NR⁸R⁹, wherein said C₁₋₆alkyl, C₂₋₆alkynyl,C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocyclyl, and 5-10membered heteroaryl are optionally substituted with 1-5 R¹⁰ groups; R²is hydrogen, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₁₀cycloalkyl, or 3-12membered heterocyclyl, wherein said C₁₋₆alkyl, C₁₋₆heteroalkyl,C₃₋₁₀cycloalkyl, and 3-12 membered heterocyclyl are optionallysubstituted with 1-5 R¹⁰ groups; R³ and R⁴ are independently hydrogen,C₁₋₆alkyl, C₁₋₆heteroalkyl, —NR⁸R⁹, NR⁸C(O)R⁹, —NR⁸C(O)OR⁹, C₆₋₁₀aryl,C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl,—C(O)R⁷, —C(O)OR⁷, —C(O)NR⁸R⁹, —OC(O)NR⁸R⁹, —CN, or —SO₂R⁷, wherein saidC₁₋₆alkyl, C₁₋₆heteroalkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 memberedheteroaryl, and 3-12 membered heterocyclyl are optionally substitutedwith 1-5 R¹⁰ groups; R⁵ is hydrogen, C₁₋₆alkyl, —(CH₂CH₂O)_(p)R⁷,C₁₋₆heteroalkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl,or 3-12 membered heterocyclyl, wherein said C₁₋₆alkyl, C₁₋₆heteroalkyl,C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 3-12 memberedheterocyclyl are optionally substituted with 1-5 R¹⁰ groups; R⁶ ishydrogen or halo; each R⁷ is independently hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl,or 5-10 membered heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl,C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are optionally substituted with from 1-5 R¹⁰; eachR⁸ and R⁹ are independently hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl, or 5-10 memberedheteroaryl, or R⁸ and R⁹ together with the atoms to which they areattached form a 3-12 membered heterocycle, wherein said C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl,and 5-10 membered heteroaryl are optionally substituted with 1-5 R¹⁰;each R¹⁰ is independently C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl,3-12 membered heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halo,oxo, —OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b),—S(O)_(q)R^(a), —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂,or two R¹⁰ groups form a fused, spiro, or bridged C₃₋₁₀ cycloalkyl or3-12 membered heterocyclyl, wherein each C₁₋₆alkyl, O₁₋₆ heteroalkyl,C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀aryl, 3-12 membered heterocycle, and5-10 membered heteroaryl is optionally substituted with 1-5 R²⁰ groups;each R^(a) and R^(b) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl,C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 membered heterocyclyl, C₆₋₁₀aryl,5-10 membered heteroaryl, or R^(a) and R^(b) together with the atoms towhich they are attached form a 3-12 membered heterocyclyl, wherein saidC₁₋₆alkyl, C₂₋₆ alkenyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 3-12 memberedheterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl is optionallysubstituted with 1-5 R²⁰ groups; each R²⁰ is independently C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, C₁₋₆ heteroalkyl, 3-12 membered heterocyclyl, C₆-C₁₀aryl, 5-10 membered heteroaryl, hydroxyl, O₁₋₆ alkoxy, amino, —CN,—C(O)H, —C(O)NH₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ alkyl)₂, —COOH,—C(O)C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl, or halogen; n is 0, 1, or 2; p is 0,1, or 2; q is 0, 1, or 2; the C₁₋₆heteroalkyl is an alkyl group in whichone to three of the carbon atoms are each independently replaced withthe same or different heteroatomic group; wherein C₁₋₆heteroalkyl has1-6 carbon atoms; and wherein the heteroatomic group is independentlyselected from nitrogen, sulfur, phosphorus, oxygen, —N(O)—, —S(O)—, and—S(O)₂—; the 3-12 membered heterocyclyl is a non-aromatic group having asingle ring or multiple rings; wherein the 3-12 membered heterocyclylhas one to three heteroatoms independently selected from nitrogen,sulfur, phosphorus, —N(O)—, —S(O)—, and —S(O)₂—; wherein the multiplerings may be fused, bridged, or spiro; and the 5-10 membered heteroarylis an aromatic group having a single ring or multiple rings; wherein the5-10 membered heteroaryl contains one to three ring heteroatomsindependently selected from nitrogen, oxygen, sulfur, —N(O)—, —S(O)—,and —S(O)₂.
 2. The compound of claim 1, according to Formula (IIa):

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein: R² is hydrogen or C₁₋₃alkyl; R³ is hydrogen or C₁₋₃alkyl; R⁴is hydrogen; R⁵ is C₁₋₃alkyl, wherein said C₁₋₃alkyl is optionallysubstituted with a 5-6 membered heterocyclyl; or a pharmaceuticallyacceptable salt thereof.
 4. The compound of claim 1, wherein: R² ishydrogen, methyl, or ethyl; R³ is hydrogen or methyl; R⁴ is hydrogen;and R⁵ is hydrogen, methyl,

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein: R² is hydrogen; and R³ is C₁₋₃alkyl; or a pharmaceuticallyacceptable salt thereof.
 6. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is hydrogen.
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is methyl.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is hydrogen.
 9. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ ismethyl.
 10. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁶ is Cl.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is 3-12 memberedheterocyclyl, or 5-10 membered heteroaryl; and wherein 3-12 memberedheterocyclyl, or 5-10 membered heteroaryl is optionally substituted with1-2 R¹⁰.
 12. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹ is

substituted with 1-2 R¹⁰.
 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is

substituted with two groups selected from C₁₋₄alkyl and C₁₋₄alkoxyl. 14.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is


15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from:


16. The compound of claim 1, wherein —C(O)R¹ is selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.18. The pharmaceutical composition of claim 17, further comprising oneor more additional therapeutic agents.
 19. The pharmaceuticalcomposition of claim 18, wherein the additional therapeutic agent is achemotherapeutic drug.
 20. The pharmaceutical composition of claim 18,wherein the additional therapeutic agent is an immune checkpointinhibitor, wherein the immune checkpoint inhibitor is selected fromanti-PD-1 antibody, anti-PD-L1 antibody, and anti PD-1/PD-L1 interactioninhibitor.